An Alphavirus -derived replicon RNA vaccine induces SARS-CoV-2 neutralizing antibody and T cell responses in mice and nonhuman primates
Open accessAbstract
-derived replicon RNA vaccine candidate, repRNA-CoV2S, encoding the SARS-CoV-2 spike (S) protein. The RNA replicons were formulated with lipid inorganic nanoparticles (LIONs) that were designed to enhance vaccine stability, delivery, and immunogenicity. We show that a single intramuscular injection of the LION/repRNA-CoV2S vaccine in mice elicited robust production of anti-SARS-CoV-2 S protein IgG antibody isotypes indicative of a type 1 T helper cell response. A prime/boost regimen induced potent T cell responses in mice including antigen-specific responses in the lung and spleen. Prime-only immunization of aged (17 months old) mice induced smaller immune responses compared to young mice, but this difference was abrogated by booster immunization. In nonhuman primates, prime-only immunization in one intramuscular injection site or prime/boost immunizations in five intramuscular injection sites elicited modest T cell responses and robust antibody responses. The antibody responses persisted for at least 70 days and neutralized SARS-CoV-2 at titers comparable to those in human serum samples collected from individuals convalescing from COVID-19. These data support further development of LION/repRNA-CoV2S as a vaccine candidate for prophylactic protection against SARS-CoV-2 infection.
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Written from the paper’s full text.
TL;DR
A prime-only alphavirus replicon RNA vaccine encoding SARS-CoV-2 spike, formulated with lipid inorganic nanoparticles (LION/repRNA-CoV2S), induced neutralizing antibodies and T cell responses in mice and pigtail macaques. The vaccine was immunogenic in aged mice and generated macaque neutralizing titers in the range of human convalescent sera, without challenge data.
Key findings
- In C57BL/6 mice, a single intramuscular dose of 10 or 1 μg LION/repRNA-CoV2S induced 100% seroconversion by day 14, with mean anti-S IgG concentrations of 200 and 109 μg/ml, respectively; pseudovirus neutralizing IC50 titers were 1:643 and 1:226. A 0.1 μg dose gave partial seroconversion (2/5 at day 14, 4/5 by day 28). After boost, anti-S IgG reached 1517, 937, and 312 μg/ml for 10, 1, and 0.1 μg groups.
- In aged BALB/c mice, 17-month-old mice had significantly lower anti-S IgG after prime than 2- and 8-month-old mice, but post-boost responses approached younger groups; LION/repRNA-CoV2S induced IgG2a:IgG1 ratios >1 in all age groups, indicating Th1-biased responses.
- In pigtail macaques, a 250 μg prime-only dose (n=3) induced seroconversion by day 10, anti-S IgG of 48, 51, and 61 μg/ml by day 42, and pseudovirus IC50 titers of 1:472, 1:108, and 1:149 by day 42. Mean PRNT80 against SARS-CoV-2/WA/2020 was 1:211 at day 42; a 50 μg prime/boost group (n=2) reached mean PRNT80 1:176 after boost. All 5 macaques had mean PRNT80 1:197, not significantly different from 7 convalescent humans (1:518, P=0.27).
- Macaques developed T cell responses to S protein by day 28, directed mostly toward S1 and RBD; no adverse reactions were observed at injection sites, though 1 animal had mild azotemia at day 14.
Methods
- Vaccine design: codon-optimized full-length SARS-CoV-2 spike (Wuhan-Hu-1 positions 21,536–25,384) fused to a C-terminal v5 tag was cloned into a Venezuelan equine encephalitis virus TC-83 replicon; repRNA was mixed 1:1 with LION, a cationic squalene emulsion containing superparamagnetic iron oxide nanoparticles and DOTAP.
- Animal studies: C57BL/6 and BALB/c mice (n=5/group) received intramuscular doses of 10, 1, or 0.1 μg; pigtail macaques received 250 μg prime-only (n=3, 5 injection sites) or 50 μg prime/boost (n=2). Immunogenicity was measured by anti-S IgG ELISA, pseudovirus neutralization, PRNT80 against wild-type SARS-CoV-2/WA/2020, IFN-γ ELISpot, and intracellular cytokine staining.
- Analysis: group comparisons used one-way ANOVA with Tukey’s test, Student’s t test, Mann-Whitney U test, or Wilcoxon test; significance was p<0.05. Mouse group sizes were based on power analyses; macaque group sizes were limited by animal availability; no blinding was used.
Limitations
- Stated by the paper: conclusions are drawn in the absence of challenge data, from a limited number of animals, and at time points where T cell responses showed great variability; larger studies are needed to evaluate safety, kinetics, durability, and protection, including absence of immune enhancement of disease.
- Stated by the paper: the 250 μg macaque dose was given concurrently across five injection sites, so it cannot be ruled out that immunogenicity and safety would differ with a single bolus injection; larger group sizes are needed to confirm the comparison with human convalescent titers.
- Evident from the text: macaques were five adult males only, no blinding was used, and the macaque immunogenicity experiment was performed once; no viral challenge was performed to test protection.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
18 of 28 cited sources checked · 6 supported · 0 flagged · accuracy not yet measured
- Premisecitation
Human neutralizing antibodies protected mice challenged with SARS-CoV and MERS-CoV.
“previous reports have shown that human neutralizing antibodies protected mice challenged with SARS-CoV (12–14) and Middle East respiratory syndrome (MERS)-CoV (15)”
Quote in the paperSubstantial claim2 of 4 sources checked- cites [12] Menachery V. D., Yount B. L. J. Jr., Sims A. C., Debbink K., Agnihothram S. S., Gralinski L. E., Graham R. L., Scobey T., Plante J. A., Royal S. R., Swanstrom J., Sheahan T. P., Pickles R. J., Corti D., Randell S. H., Lanzavecchia A., Marasco W. A., Baric R. S., SARS-like WIV1-CoV poised for human emergence. Proc. Natl. Acad. Sci. U.S.A. 113, 3048– 3053 (2016). 10.1073/pnas.1517719113 26976607 PMC4801244 source
- cites [13] Rockx B., Corti D., Donaldson E., Sheahan T., Stadler K., Lanzavecchia A., Baric R., Structural basis for potent cross-neutralizing human monoclonal antibody protection against lethal human and zoonotic severe acute respiratory syndrome coronavirus challenge. J. Virol. 82, 3220– 3235 (2008). 10.1128/JVI.02377-07 18199635 PMC2268459 source
- cites [14] Traggiai E., Becker S., Subbarao K., Kolesnikova L., Uematsu Y., Gismondo M. R., Murphy B. R., Rappuoli R., Lanzavecchia A., An efficient method to make human monoclonal antibodies from memory B cells: Potent neutralization of SARS coronavirus. Nat. Med. 10, 871– 875 (2004). 10.1038/nm1080 15247913 PMC7095806 source
- cites [15] Corti D., Zhao J., Pedotti M., Simonelli L., Agnihothram S., Fett C., Fernandez-Rodriguez B., Foglierini M., Agatic G., Vanzetta F., Gopal R., Langrish C. J., Barrett N. A., Sallusto F., Baric R. S., Varani L., Zambon M., Perlman S., Lanzavecchia A., Prophylactic and postexposure efficacy of a potent human monoclonal antibody against MERS coronavirus. Proc. Natl. Acad. Sci. U.S.A. 112, 10473– 10478 (2015). 10.1073/pnas.1510199112 26216974 PMC4547275 source
- Premisecitation
Protection against SARS-CoV-2 is thought to be mediated by neutralizing antibodies against the S protein.
“Protection is thought to be mediated by neutralizing antibodies against the S protein (7, 8)”
Quote in the paperSubstantial claim2 of 2 sources checked- cites [7] Walls A. C., Xiong X., Park Y.-J., Tortorici M. A., Snijder J., Quispe J., Cameroni E., Gopal R., Dai M., Lanzavecchia A., Zambon M., Rey F. A., Corti D., Veesler D., Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion. Cell 176, 1026– 1039.e15 (2019). 10.1016/j.cell.2018.12.028 30712865 PMC6751136 source
The Introduction (page not provided) calls the S glycoprotein the main target of neutralizing antibodies and describes antibodies from SARS-CoV and MERS-CoV survivors. The paper does not address SARS-CoV-2 or establish that these antibodies mediate protection against it. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [8] Pinto D., Park Y.-J., Beltramello M., Walls A. C., Tortorici M. A., Bianchi S., Jaconi S., Culap K., Zatta F., De Marco A., Peter A., Guarino B., Spreafico R., Cameroni E., Case J. B., Chen R. E., Havenar-Daughton C., Snell G., Telenti A., Virgin H. W., Lanzavecchia A., Diamond M. S., Fink K., Veesler D., Corti D., Structural and functional analysis of a potent sarbecovirus neutralizing antibody. bioRxiv (2020). 10.1101/2020.04.07.023903 source
- Premisecitation
mRNA and DNA vaccines may not be able to induce protective efficacy in humans after a single immunization because they typically require multiple administrations over an extended period.
“However, mRNA and DNA vaccines may not be able to induce protective efficacy in humans after a single immunization since, similar to inactivated and recombinant subunit protein vaccines, they typically require multiple administrations over an extended period of time to become effective (19).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [19] Shang W., Yang Y., Rao Y., Rao X., The outbreak of SARS-CoV-2 pneumonia calls for viral vaccines. Vaccines (Basel) 5, 18 (2020). 32194995 PMC7060195 source
The paper says subunit vaccines require multiple booster shots, and Table 1 reports lower immune responses in humans for DNA vaccines. It does not say that both DNA and mRNA vaccines typically require multiple administrations over an extended period, or that a single dose cannot provide protective efficacy in humans. The indexed copy provides section labels but no page numbers. (LLM, conf=0.85)
Experimental — accuracy not yet measured
- Premisecitation
In rhesus macaques immunized with DNA vaccine candidates, titers between 1:60 and 1:200 correlated with complete protection from disease.
“titers between 1:60 and 1:200 correlated with complete protection from disease.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [53] Yu J., Tostanoski L. H., Peter L., Mercado N. B., McMahan K., Mahrokhian S. H., Nkolola J. P., Liu J., Li Z., Chandrashekar A., Martinez D. R., Loos C., Atyeo C., Fischinger S., Burke J. S., Slein M. D., Chen Y., Zuiani A., N Lelis F. J., Travers M., Habibi S., Pessaint L., Van Ry A., Blade K., Brown R., Cook A., Finneyfrock B., Dodson A., Teow E., Velasco J., Zahn R., Wegmann F., Bondzie E. A., Dagotto G., Gebre M. S., He X., Jacob-Dolan C., Kirilova M., Kordana N., Lin Z., Maxfield L. F., Nampanya F., Nityanandam R., Ventura J. D., Wan H., Cai Y., Chen B., Schmidt A. G., Wesemann D. R., Bari source
The Immune correlates of vaccine-induced protection section reports higher neutralizing-antibody titers in completely protected than partially protected vaccinated macaques; it defines complete protection as no detectable sgmRNA after challenge. The paper does not identify titers of 1:60 to 1:200 as a range associated with complete protection. The titers of 74 and 170 reported in Construction and immunogenicity are group medians, not protection thresholds (pages not specified in our copy). (LLM, conf=0.88)
Experimental — accuracy not yet measured
- Findingown data
repRNA-CoV2S efficiently expressed the v5-tagged S protein in BHK cells.
“Using immunofluorescence and Western blot we demonstrated efficient expression of the v5-tagged S protein in BHK cells (Fig. 1B,C).”
Quote in the paperNot a substantial claim
- Findingown data
Mice receiving a 10, 1, or 0.1 μg prime/boost exhibited robust splenic T cell responses with mean IFN-γ spots/10^6 cells of 1698, 650, and 801, respectively.
“Mice receiving a 10, 1, or 0.1 μg prime/boost exhibited robust splenic T cell responses with mean IFN-γ spots/106 cells of 1698, 650, and 801, respectively (Fig. 2E).”
Quote in the paperSubstantial claim - Findingown data
A single site intramuscular immunization of C57BL/6 mice with 10 or 1 μg LION/repRNA-CoV2S induced 100% seroconversion by 14 days post-immunization.
“A single site intramuscular immunization of C57BL/6 mice (n=5/group) with 10 or 1 μg of LION/repRNA-CoV2S induced 100% seroconversion by 14 days post-immunization”
Quote in the paperSubstantial claim - Findingown data
There was a trend toward higher doses inducing greater Th1-biased responses as indicated by higher IgG2c:IgG1 ratios.
“there was a trend toward higher doses inducing greater Th1-biased responses as indicated by higher IgG2c:IgG1 ratios (Fig. 2D).”
Quote in the paperNot a substantial claim - Findingown data
No differences were observed between the 2- and 8-month old mice in antibody responses.
“No differences were observed between the 2- and 8-month old mice (Fig. 3A).”
Quote in the paperSubstantial claim - Findingown data
The 10 and 1 μg doses induced anti-S IgG mean binding concentrations of 200 and 109 μg/ml, respectively, at 14 days.
“robust anti-S IgG with mean binding concentrations of 200 and 109 μg/ml, respectively”
Quote in the paperSubstantial claim - Findingown data
Significantly lower antibody responses were observed in 17-month old BALB/c mice at both 10 and 1 μg doses following a prime immunization compared to 2- and 8-month old mice.
“Significantly lower antibody responses were observed in the 17-month old mice at both doses following a prime immunization (Fig. 3A), when compared to 2- and 8-month old mice”
Quote in the paperSubstantial claim - Findingown data
All three doses induced Th1-biased immune responses indicated by higher IgG2c responses compared to IgG1.
“While all doses induced Th1-biased immune responses indicated by higher IgG2c responses when compared to IgG1 (Fig. 2C)”
Quote in the paperNot a substantial claim - Findingown data
LION-formulated repRNA showed substantial protection from RNase-catalyzed degradation compared to unformulated repRNA after a concentrated RNase challenge.
“Gel electrophoresis analysis of LION-formulated repRNA molecules extracted by phenol-chloroform treatment after a concentrated RNase challenge showed substantial protection from RNase-catalyzed degradation compared to unformulated repRNA (Fig. 1G).”
Quote in the paperNot a substantial claim - Findingown data
The LION formulation is colloidally stable for at least 3 months when stored at 4 and 25°C.
“The formulation is colloidally stable for at least 3 months when stored at 4 and 25°C (Fig. 1E).”
Quote in the paperNot a substantial claim - Findingown data
BHK cells transfected with repRNA-CoV2S expressed endogenous S protein reactive with natural SARS-CoV-2 immune sera.
“we demonstrated endogenous expression of S protein in BHK cells, reactive with natural SARS-CoV-2 immune sera (Fig. 1C).”
Quote in the paperSubstantial claim - Findingown data
Serum chemistries revealed no abnormal findings except for mild azotemia in 1 animal at 14 days post vaccination.
“serum chemistries revealed no abnormal findings, except for mild azotemia (mildly elevated blood urea nitrogen and creatinine) in 1 animal at 14 days post vaccination (Fig. S2C).”
Quote in the paperNot a substantial claim - Findingown data
LION has an intensity-weighted average diameter of 52 nm (PDI = 0.2) measured by dynamic light scattering.
“LION has an intensity-weighted average diameter of 52 nm (PDI = 0.2) measured by dynamic light scattering.”
Quote in the paperNot a substantial claim - Findingown data
Modest increased frequencies of cytokine or IFN-γ producing S-specific effector memory CD8+ T cells were observed by 42 days post vaccination.
“Finally, modest increased frequencies of cytokine or IFN-γ producing S-specific effector memory CD8+ T cells were observed by 42 days post vaccination (Fig. 5C,D and Fig. S6).”
Quote in the paperNot a substantial claim - Findingown data
LION/repRNA-CoV2S induces S-specific T cell responses in mice and macaques.
“Additionally, we demonstrated that LION/repRNA-CoV2S induces S-specific T cell responses in mice and macaques.”
Quote in the paperSubstantial claim - Findingown data
The vaccine induced Th1-biased antibody and T cell responses in both young and aged mice as well as pigtail macaques.
“Critically, the vaccine induced Th1-biased antibody and T cell responses in both young and aged mice as well as pigtail macaques”
Quote in the paperSubstantial claim - Findingown data
Intracellular cytokine staining revealed modest increases in cytokine-producing CD8+ T cells.
“Further evaluation of the T cell response by intracellular cytokine staining revealed modest increases in cytokine-producing CD8+ T cells (Fig. 5C and Fig. S5).”
Quote in the paperNot a substantial claim - Findingown data
A prime-only immunization with 50 and 250 μg of LION/repRNA-CoV2S induced mean PRNT80 titers by day 28 postvaccination of 1:32 and 1:66, respectively.
“A prime-only immunization with 50 and 250 μg of LION/repRNA-CoV2S induced mean PRNT80 titers by day 28 postvaccination of 1:32 and 1:66, respectively (Fig. 4D).”
Quote in the paperSubstantial claim - Findingown data
Fourteen days after a booster immunization, the 50 μg dose group developed similar concentrations of anti-S IgG (18 and 37 μg/ml) as the 250 μg dose prime-only group at this time point (48, 51, and 61 μg/ml).
“However, 14 days after a booster immunization, the 50 μg dose group developed similar concentrations of anti-S IgG (18 and 37 μg/ml) as the 250 μg dose prime-only group at this time point (48, 51, and 61 μg/ml) (Fig. 4A).”
Quote in the paperSubstantial claim - Findingown data
The T cell response was directed mostly toward the S1 and RBD regions of SARS-CoV-2 S protein.
“Similar to findings in our vaccinated mice, the T cell response was directed mostly toward the S1 and RBD regions of SARS-CoV-2 S protein (Fig. 5B).”
Quote in the paperNot a substantial claim - Findingown data
All 5 macaques developed T cell responses to SARS-CoV-2 S protein by day 28.
“ELISpot analyses of peripheral blood mononuclear cells (PMBCs) collected 10, 14, 28 and 42 days post immunization, showed that all 5 macaques developed T cell responses to SARS-CoV-2 S protein by day 28 (Fig. 5A).”
Quote in the paperSubstantial claim - Interpretationcitation
Protection against SARS-CoV-2 could be mediated through anti-S antibodies.
“suggesting that protection against SARS-CoV-2 could be mediated through anti-S antibodies.”
Quote in the paperSubstantial claim - Interpretationcitation
An effective COVID-19 vaccine will likely need to induce, at the very least, Th1-biased immune responses comprised of SARS-CoV-2-specific neutralizing antibodies.
“Therefore, an effective COVID-19 vaccine will likely need to induce, at the very least, Th1-biased immune responses comprised of SARS-CoV-2-specific neutralizing antibodies.”
Quote in the paperSubstantial claim - Premisecitation
repRNA vaccines often require only a single administration to be effective.
“Given that repRNA vaccines often require only a single administration to be effective (30)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [30] Strauss J. H., Strauss E. G., The alphaviruses: Gene expression, replication, and evolution. Microbiol. Rev. 58, 491– 562 (1994). 10.1128/MMBR.58.3.491-562.1994 7968923 PMC372977 source
- Interpretationreasoning
A 250 μg prime-only dose or a 50 μg prime/boost immunization with LION/repRNA-CoV2S induced concentrations of neutralizing antibodies that would be sufficient to protect nonhuman primates from infection and disease.
“These data suggest that a 250 μg prime-only dose or a 50 μg prime/boost immunization with the LION/repRNA-CoV2S vaccine induced concentrations of neutralizing antibodies that would be sufficient to protect nonhuman primates from infection and disease.”
Quote in the paperSubstantial claim - Interpretationown data
Together, the results demonstrate potential for LION/repRNA-CoV2S to induce rapid immune protection from SARS-CoV-2 infection.
“Together, our results demonstrate potential for LION/repRNA-CoV2S, which will enter clinical development under the name HDT-301, to induce rapid immune protection from SARS-CoV-2 infection.”
Quote in the paperSubstantial claim- Rests on an assumption: Immune responses and protection observed in mice and pigtail macaques are predictive of protective immunity in humans.
- Classified as probably not a substantial claim. 12
- May combine two claims. 30
- The quote only partly states this claim. 2
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe SARS-CoV-2 Spike protein mediates binding of coronaviruses to ACE2 on the surface of various cell types including epithelial cells of the pulmonary alveolus.
“The S protein mediates binding of coronaviruses to angiotensin converting enzyme 2 (ACE2) on the surface of various cell types including epithelial cells of the pulmonary alveolus (4–6).”
Quote in the paperNot a substantial claim2 of 3 sources checked- cites [4] Hamming I., Timens W., Bulthuis M. L. C., Lely A. T., Navis G., van Goor H., Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J. Pathol. 203, 631– 637 (2004). 10.1002/path.1570 15141377 PMC7167720 source
- cites [5] Letko M., Marzi A., Munster V., Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat. Microbiol. 5, 562– 569 (2020). 10.1038/s41564-020-0688-y 32094589 PMC7095430 source
The Results (‘Receptor usage of SARS-CoV-2’; page not provided) report that a spike chimera containing the SARS-CoV-2 receptor-binding domain entered cells expressing human ACE2. The paper does not establish ACE2 binding on pulmonary alveolar epithelial cells. Its Main section also identifies a different receptor for MERS-CoV, so the ACE2 statement does not apply to coronaviruses generally. (LLM, conf=0.87)
Experimental — accuracy not yet measured - cites [6] Walls A. C., Park Y.-J., Tortorici M. A., Wall A., McGuire A. T., Veesler D., Structure, Function, and Antigenicity of the SARS-CoV-2 Spike Glycoprotein. Cell 181, 281– 292.e6 (2020). 10.1016/j.cell.2020.02.058 32155444 PMC7102599 source
The Introduction and Results section “ACE2 Is an Entry Receptor for SARS-CoV-2” establish that SARS-CoV-2 spike binds ACE2 and can mediate entry into ACE2-expressing cells. The same Results section identifies ACE2 at the surface of type II pneumocytes—alveolar epithelial cells—but makes that statement about SARS-CoV, not SARS-CoV-2. The cited paper therefore does not directly establish SARS-CoV-2 spike binding on those lung cells. (LLM, conf=0.84)
Experimental — accuracy not yet measured
May combine two claims.
PremisecitationrepRNA acts as its own adjuvant, eliciting more robust immune responses after a single dose relative to conventional mRNA which typically requires multiple, 1,000-fold higher doses.
“As a result, repRNA acts as its own adjuvant, eliciting more robust immune responses after a single dose, relative to conventional mRNA which typically requires multiple, 1,000-fold higher doses (29).”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [29] Vogel A. B., Lambert L., Kinnear E., Busse D., Erbar S., Reuter K. C., Wicke L., Perkovic M., Beissert T., Haas H., Reece S. T., Sahin U., Tregoning J. S., Self-Amplifying RNA Vaccines Give Equivalent Protection against Influenza to mRNA Vaccines but at Much Lower Doses. Mol. Ther. 26, 446– 455 (2018). 10.1016/j.ymthe.2017.11.017 29275847 PMC5835025 source
The Discussion (page unavailable) says self-amplifying RNA provides additional immune stimuli, consistent with the adjuvant-like part of the claim. But the Results report equivalent protection at a 64-fold lower dose, not a 1,000-fold lower dose, and Figure 1 describes a prime-boost regimen for both RNA vaccines, not a single dose of self-amplifying RNA versus multiple doses of conventional mRNA. (LLM, conf=0.91)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA recent study indicates SARS-CoV-2-specific T cell responses may be associated with better recovery from COVID-19.
“A recent study indicates SARS-CoV-2-specific T cell responses may be associated with better recovery from COVID-19 (57).”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [57] Grifoni A., Weiskopf D., Ramirez S. I., Mateus J., Dan J. M., Moderbacher C. R., Rawlings S. A., Sutherland A., Premkumar L., Jadi R. S., Marrama D., de Silva A. M., Frazier A., Carlin A. F., Greenbaum J. A., Peters B., Krammer F., Smith D. M., Crotty S., Sette A., Targets of T Cell Responses to SARS-CoV-2 Coronavirus in Humans with COVID-19 Disease and Unexposed Individuals. Cell 181, 1489– 1501.e15 (2020). 10.1016/j.cell.2020.05.015 32473127 PMC7237901 source
The Results (CD4+ and CD8+ T Cell Responses; page unavailable) report SARS-CoV-2-specific T cell responses in recovered COVID-19 patients. The study did not compare patients with better and worse recovery, so it does not establish an association between those responses and better recovery. (LLM, conf=0.85)
Experimental — accuracy not yet measured
May combine two claims.
Findingown dataLION/repRNA-CoV2S elicited modest but detectable T cell responses in macaques, consistent with previous studies of SARS-CoV-2 S-targeted DNA and live viral vector vaccines tested in nonhuman primates.
“Our findings demonstrate that LION/repRNA-CoV2S elicited modest but detectable T cell responses in macaques (Fig. 5), an outcome that is consistent with previous studies of SARS-CoV-2 S-targeted DNA and live viral vector vaccines tested in nonhuman primates (53, 58).”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [53] Yu J., Tostanoski L. H., Peter L., Mercado N. B., McMahan K., Mahrokhian S. H., Nkolola J. P., Liu J., Li Z., Chandrashekar A., Martinez D. R., Loos C., Atyeo C., Fischinger S., Burke J. S., Slein M. D., Chen Y., Zuiani A., N Lelis F. J., Travers M., Habibi S., Pessaint L., Van Ry A., Blade K., Brown R., Cook A., Finneyfrock B., Dodson A., Teow E., Velasco J., Zahn R., Wegmann F., Bondzie E. A., Dagotto G., Gebre M. S., He X., Jacob-Dolan C., Kirilova M., Kordana N., Lin Z., Maxfield L. F., Nampanya F., Nityanandam R., Ventura J. D., Wan H., Cai Y., Chen B., Schmidt A. G., Wesemann D. R., Bari source
- cites [58] N. Van Doremalen, T. Lambe, A. Spencer, S. Belij-rammerstorfer, J. N. Purushotham, J. R. Port, V. Avanzato, T. Bushmaker, M. Ulaszewska, F. Feldmann, E. R. Allen, H. Sharpe, J. Schulz, M. Holbrook, A. Okumura, K. Meade-white, C. Bissett, C. Gilbride, B. N. Williamson, R. Rosenke, D. Long, A. Ishwarbhai, R. Kailath, L. Rose, S. Morris, C. Powers, J. Lovaglio, P. W. Hanley, D. Scott, G. Saturday, E. De Wit, C. Sarah, V. J. Munster, ChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques. bioRxiv 10.1101/2020.05.13.093195 (2020). source
May combine two claims.
PremisecitationIn rhesus macaques, IC50 titers as low as 1:8 were associated with protection from re-infection, and IC50 titers as low as 1:50 were associated with reduced viral load and protection from lung pathology.
“In the former report, IC50 titers as low as 1:8 were associated with protection from re-infection while in the latter, IC50 titers as low as 1:50 were associated with reduced viral load and protection from lung pathology.”
Quote in the paperNot a substantial claim2 of 2 sources checked- cites [51] L. Bao, W. Deng, H. Gao, C. Xiao, J. Liu, J. Xue, Q. Lv, J. Liu, P. Yu, Y. Xu, F. Qi, Y. Qu, F. Li, Z. Xiang, H. Yu, S. Gong, M. Liu, G. Wang, S. Wang, Z. Song, W. Zhao, Y. Han, L. Zhao, X. Liu, Q. Wei, C. Qin, Reinfection could not occur in SARS-CoV-2 infected rhesus macaques, bioRxiv, 2020.03.13.990226 (2020). source
The ‘former report’ is this paper; the ‘latter’ finding is attributed to a different report and is not assessed here. In ‘SARS-CoV-2-infection protect monkeys from reinfection’ (page unavailable), the paper reports no detectable viral load after rechallenge and suggests neutralizing antibodies might protect against reinfection. Our copy does not establish the specific IC50 titer of 1:8; the Table 1 text is garbled. (LLM, conf=0.82)
Experimental — accuracy not yet measured - cites [52] Gao Q., Bao L., Mao H., Wang L., Xu K., Yang M., Li Y., Zhu L., Wang N., Lv Z., Gao H., Ge X., Kan B., Hu Y., Liu J., Cai F., Jiang D., Yin Y., Qin C., Li J., Gong X., Lou X., Shi W., Wu D., Zhang H., Zhu L., Deng W., Li Y., Lu J., Li C., Wang X., Yin W., Zhang Y., Qin C., Development of an inactivated vaccine candidate for SARS-CoV-2. Science 369, 77– 81 (2020). 10.1126/science.abc1932 32376603 PMC7202686 source
May combine two claims.
PremisecitationFollowing natural infection of humans with SARS-CoV, neutralizing antibody and memory B cell responses in some individuals are short lived (~3 years), whereas memory T cells persist for at least 6 years.
“Following natural infection of humans with the related SARS-CoV, neutralizing antibody and memory B cell responses in some individuals are reported to be short lived (~ 3 years), whereas memory T cells persist for at least 6 years (54–56)”
Quote in the paperSubstantial claim1 of 3 sources checked- cites [54] Tang F., Quan Y., Xin Z.-T., Wrammert J., Ma M.-J., Lv H., Wang T.-B., Yang H., Richardus J. H., Liu W., Cao W.-C., Lack of peripheral memory B cell responses in recovered patients with severe acute respiratory syndrome: A six-year follow-up study. J. Immunol. 186, 7264– 7268 (2011). 10.4049/jimmunol.0903490 21576510 source
- cites [55] Ng O.-W., Chia A., Tan A. T., Jadi R. S., Leong H. N., Bertoletti A., Tan Y.-J., Memory T cell responses targeting the SARS coronavirus persist up to 11 years post-infection. Vaccine 34, 2008– 2014 (2016). 10.1016/j.vaccine.2016.02.063 26954467 PMC7115611 source
The Introduction reports that SARS-specific memory T cells persisted for up to six years after recovery, and the Conclusion reports their detection at nine and eleven years. The Introduction also says SARS-specific antibody levels were undetectable at six years, but our copy does not establish that neutralizing antibodies or memory B cells were short-lived at approximately three years. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [56] Chen H., Hou J., Jiang X., Ma S., Meng M., Wang B., Zhang M., Zhang M., Tang X., Zhang F., Wan T., Li N., Yu Y., Hu H., Yang R., He W., Wang X., Cao X., Response of memory CD8+ T cells to severe acute respiratory syndrome (SARS) coronavirus in recovered SARS patients and healthy individuals. J. Immunol. 175, 591– 598 (2005). 10.4049/jimmunol.175.1.591 15972696 source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAnti-S T-cell responses to SARS- and MERS-CoVs contribute toward viral clearance in normal as well as aged mice infected with SARS- or MERS-CoV, respectively.
“anti-S T-cell responses to the related SARS- and MERS-CoVs contribute toward viral clearance in normal as well as aged mice infected with SARS- or MERS-CoV, respectively (43–45).”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [43] Zhao J., Zhao J., Perlman S., T cell responses are required for protection from clinical disease and for virus clearance in severe acute respiratory syndrome coronavirus-infected mice. J. Virol. 84, 9318– 9325 (2010). 10.1128/JVI.01049-10 20610717 PMC2937604 source
The Results identify S366 as an epitope of the SARS-CoV spike protein and report that transferring S366-specific CD8 T cells accelerated viral clearance in infected BALB/c mice. This supports the SARS-CoV portion of the claim, but the paper does not establish the claimed effect in aged mice or in MERS-CoV-infected mice. (LLM, conf=0.88)
Experimental — accuracy not yet measured - cites [44] Channappanavar R., Zhao J., Perlman S., T cell-mediated immune response to respiratory coronaviruses. Immunol. Res. 59, 118– 128 (2014). 10.1007/s12026-014-8534-z 24845462 PMC4125530 source
The sections on T-cell responses in infected animals and on memory T cells report that spike-specific responses contribute to SARS-CoV clearance in young mice and can improve clearance or protection in older mice. The MERS-CoV passage reports spike-specific CD8 T cells and a role for T cells in clearance in susceptible mice, but does not establish the claimed effect in aged MERS-CoV-infected mice. Page numbers are unavailable in our copy. (LLM, conf=0.86)
Experimental — accuracy not yet measured - cites [45] Channappanavar R., Fett C., Zhao J., Meyerholz D. K., Perlman S., Virus-specific memory CD8 T cells provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection. J. Virol. 88, 11034– 11044 (2014). 10.1128/JVI.01505-14 25056892 PMC4178831 source
The Results report that responses to the SARS-CoV spike epitopes S436 and S525 accelerated viral clearance in 8- to 10-month-old mice. The Discussion says virus-specific CD8 T cells are important for MERS-CoV clearance, but does not establish that those cells target spike or that the finding applies to both young and aged MERS-CoV-infected mice. (LLM, conf=0.87)
Experimental — accuracy not yet measured
The quote only partly states this claim.
Findingnone givenA prime-only replicating RNA vaccine delivered with lipid inorganic nanoparticles induces neutralizing antibody and T cell responses against SARS-CoV-2 in aged mice and macaques.
“A prime-only replicating RNA vaccine delivered with lipid inorganic nanoparticles induces neutralizing antibody and T cell responses against SARS-CoV-2 in aged mice and macaques.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMice receiving a 10 or 1 μg prime/boost exhibited robust splenic T cell responses with mean IFN-γ spots/10^6 cells of 1179, 1328, and 946 in the 10 μg groups and 458, 409, and 1231 in the 1 μg groups for the 17-, 8-, and 2-month old mice, respectively.
“Mice receiving a 10 or 1 μg prime/boost exhibited robust splenic T cell responses with mean IFN-γ spots/106 cells of 1179, 1328, and 946 in the 10 μg groups and 458, 409, and 1231 in the 1 μg groups for the 17-, 8-, and 2-month old mice, respectively (Fig. 3B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataLION maintained full integrity of repRNA molecules and complex size at 1, 4 and 7 days after mixing.
“LION maintained full integrity of the repRNA molecules (Fig. 1H) and complex size (Fig. 1I) at all time points.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataFollowing a boost immunization, 17-month old mice developed significantly higher antibody responses relative to their prime responses, approaching post-boost responses seen in 8- and 2-month old mice; antibody responses in the 17-month old 1 μg dose group were still significantly lower than the 2-month-old counterpart.
“However, following a boost immunization, the 17-month old mice developed significantly higher antibody responses relative to their prime responses (p=0.001 and p<0.0001, for the 10 and 1 μg doses, respectively), approaching the post-boost responses seen in the 8- and 2-month old mice; antibody responses in the 17-month old 1 μg dose group were still significantly lower than the 2-month-old”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAll three dose groups responded to a boost immunization, reaching anti-S mean IgG concentrations of 1517, 937, and 312 μg/ml for 10, 1, and 0.1 μg, respectively.
“All three dose groups, 10, 1, and 0.1 μg, responded to a boost immunization, reaching anti-S mean IgG concentrations of 1517, 937, and 312 μg/ml, respectively (Fig. 2A).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataNo significant differences were observed between age groups in T cell responses, but more variability was observed in the 17-month old mice relative to the 8- and 2-month old mice.
“No significant differences were observed between age groups, however, more variability in T cell responses were observed in the 17-month old mice relative to the 8- and 2-month old mice.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataBoth the 10 and 1 μg prime-only doses induced neutralizing antibodies with mean IC50 of 1:643 and 1:226, respectively, significantly higher than titers induced by the 0.1 μg dose (p=0.03 and p=0.02).
“Both the 10 and 1 μg prime-only doses induced neutralizing antibodies with mean 50% inhibitory concentrations (IC50) of 1:643 and 1:226, respectively, significantly higher than titers induced by the 0.1 μg dose (p=0.03 and p=0.02, respectively)”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataMixing anionic repRNA with cationic DOTAP on LION promotes immediate complex formation, increasing particle size to an intensity-weighted average diameter of 90 nm.
“When mixed, electrostatic association between anionic repRNA and cationic DOTAP molecules on the surface of LION promotes immediate complex formation, as confirmed by an increase in particle size to an intensity-weighted average diameter of 90 nm detected by dynamic light scattering (Fig. 1F).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataRobust T cell responses were detected in the lung and were similar between groups with mean IFN-γ spots/10^6 cells of 756, 784, and 777.
“Robust T cell responses were also detected in the lung and were similar between groups with mean IFN-γ spots/106 cells of 756, 784, and 777, respectively (Fig. 2F).”
Quote in the paperNot a substantial claimMay combine two claims. The quote only partly states this claim.
Findingown dataThe 0.1 μg dose induced partial seroconversion (2 out of 5) at day 14, increasing to 4 out of 5 by day 28.
“partial seroconversion (2 out of 5) at a 0.1 μg dose, increasing to 4 out of 5 by day 28 (Fig. 2A).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataPeptide response specificity showed a biased response toward the S1 domain in the spleen, whereas responses in the lung were more broadly distributed between the S1 and S2 domains.
“analysis of the specificity of peptide response showed a biased response toward the S1 domain of the S protein in the spleen (Fig. S1A), whereas responses in the lung were more broadly distributed between the S1 and S2 domains of the S protein (Fig. S1B).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataLION/repRNA-CoV2S induced ratios of IgG2a:IgG1 greater than 1 in all age groups of BALB/c mice, indicating a Th1-biased immune response.
“LION/repRNA-CoV2S induced ratios of IgG2a:IgG1 greater than 1 (Fig. 3C, D) in all age groups of BALB/c mice, indicating a Th1-biased immune response.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataAll three macaques immunized with the prime-only 250 μg dose seroconverted as early as day 10, with anti-S IgG concentrations continuing to increase to 48, 51, and 61 μg/ml by day 42, then appearing to plateau through at least day 70.
“all three macaques immunized with the prime-only 250 μg dose seroconverted as early as day 10, with anti-S IgG concentrations continuing to increase in these 3 animals to 48, 51, and 61 μg/ml by day 42, then appearing to plateau through at least day 70 post vaccination (Fig. 4B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataLION/repRNA-CoV2S vaccine induced robust neutralization of SARS-CoV-2 in vaccinated mice and pigtail macaques, with a mean PRNT80 titer in all 5 macaques of 1:197.
“Here, we show that the LION/repRNA-CoV2S vaccine induced robust neutralization of SARS-CoV-2 in vaccinated mice and pigtail macaques, with a mean PRNT80 titer in all 5 macaques of 1:197.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataPeak T cell responses varied between days 28-42 and were independent of the vaccine dose.
“Peak responses varied between days 28-42 and were independent of the vaccine dose.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Findingown dataNone of the pigtail macaques became severely ill or required euthanasia during the study.
“None of the animals became severely ill during the course of the study and none required euthanasia.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataSera from the three macaques immunized with the prime-only 250 μg dose neutralized pseudovirus with reciprocal IC50 titers of 1:38, 1:20 and 1:47 by day 28, increasing to 1:472, 1:108, and 1:149 by day 42; the 50 μg dose group achieved similar robust IC50 titers only after booster immunization, reaching 1:218 and 1:358 by day 42.
“sera from the three macaques immunized with the prime-only 250 μg dose neutralized pseudovirus (SARS-CoV-2 Wuhan-Hu-1 pseudotype) transduction of cells in vitro with reciprocal IC50 titers of 1:38, 1:20 and 1:47 by day 28, with IC50 titers increasing to 1:472, 1:108, and 1:149 by day 42; the 50 μg dose group achieved similar robust IC50 titers only after the booster immunization, reaching pseudov”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBy day 42, mean PRNT80 titers significantly increased to 1:176 after a booster immunization in the 50 μg dose group and to 1:211 in the prime-only 250 μg dose group (p=0.012 for both doses).
“By day 42, mean PRNT80 titers significantly increased to 1:176 after a booster immunization in the 50 μg dose group and to 1:211 in the prime-only 250 μg dose group, (Fig. 4D, p=0.012 for both doses, and Fig. S4).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFrequencies of IFN-γ producing CD4+ or CD8+ T cells showed an increasing trend in some animals by 42 days post vaccination, although changes were not significant.
“Frequencies of IFN-γ producing CD4+ or CD8+ T cells showed an increasing trend in some animals by 42 days post vaccination, although changes were not significant (Fig. 5C).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataAll 5 macaques developed PRNT80 titers within the same range as titers measured in seven convalescent humans (<1:20 to 1:1280, collected 15 to 64 days post onset of symptoms) and there was no significant difference in mean neutralizing titers between all 5 vaccinated macaques (1:197) and convalescent humans (1:518) (P=0.27).
“all 5 macaques developed PRNT80 titers within the same range as titers measured in the seven convalescent humans (<1:20 to 1:1280, collected 15 to 64 days post onset of symptoms) and there was no significant difference in mean neutralizing titers between all 5 vaccinated macaques (1:197) and convalescent humans (1:518) (P=0.27, Fig. 4D, Fig. S4, and Table S1).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBoth macaques receiving 50 μg repRNA-CoV2S seroconverted after a single dose but developed lower antibody responses with anti-S IgG concentrations of 1 and 0.5 μg/ml by day 28, compared to 7, 20, and 45 μg/ml in the 250 μg dose group at this same time point.
“Both macaques receiving 50 μg repRNA-CoV2S seroconverted after a single dose but developed lower antibody responses with anti-S IgG concentrations of 1 and 0.5 μg/ml by day 28, compared to 7, 20, and 45 μg/ml in the 250 μg dose group at this same time point (Fig. 4B).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationrepRNA vaccines mimic an alphavirus infection by triggering viral-sensing stress factors and activating innate pathways through Toll-like receptors and RIG-I to produce interferons, pro-inflammatory factors and chemotaxis of antigen-presenting cells, as well as promoting antigen cross-priming.
“repRNA vaccines mimic an alphavirus infection in that viral-sensing stress factors are triggered and innate pathways are activated through Toll-like receptors and retinoic acid inducible gene (RIG)-I to produce interferons, pro-inflammatory factors and chemotaxis of antigen-presenting cells, as well as promoting antigen cross-priming (28).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Jensen S., Thomsen A. R., Sensing of RNA viruses: A review of innate immune receptors involved in recognizing RNA virus invasion. J. Virol. 86, 2900– 2910 (2012). 10.1128/JVI.05738-11 22258243 PMC3302314 source
May combine two claims.
PremisecitationIntroduction of repRNA into cells initiates ongoing biosynthesis of antigen-encoding RNA that results in dramatically increased expression and duration that enhances humoral and cellular immune responses.
“introduction of repRNA into cells initiates ongoing biosynthesis of antigen-encoding RNA that results in dramatically increased expression and duration that enhances humoral and cellular immune responses (27).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [27] Berglund P., Smerdou C., Fleeton M. N., Tubulekas I., Liljeström P., Enhancing immune responses using suicidal DNA vaccines. Nat. Biotechnol. 16, 562– 565 (1998). 10.1038/nbt0698-562 9624688 source
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenEndpoints were selected prior to the start of each study and were selected based on the primary objective of characterizing the safety and immune responses to vaccination with a LION/repRNA-CoV2S vaccine.
“Endpoints were selected prior to the start of each study and were selected based on the primary objective of characterizing the safety and immune responses to vaccination with a LION/repRNA-CoV2S vaccine.”
Quote in the paperNot a substantial claimClassified as probably not a substantial claim.
PremisecitationC57BL/6 mice lack the IgG2a isotype.
“IgG2c isotype was selected for C57BL/6 sera due to their lack of IgG2a isotype (64)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [64] Martin R. M., Brady J. L., Lew A. M., The need for IgG2c specific antiserum when isotyping antibodies from C57BL/6 and NOD mice. J. Immunol. Methods 212, 187– 192 (1998). 10.1016/S0022-1759(98)00015-5 9672206 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenGroup sizes in the macaque study were limited by availability of animals.
“Group sizes in the macaque study were limited by availability of animals.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationBALB/C mice utilize the IgG2a isotype.
“while IgG2a is utilized for BALB/C sera (65).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [65] Aberle J. H., Aberle S. W., Kofler R. M., Mandl C. W., Humoral and cellular immune response to RNA immunization with flavivirus replicons derived from tick-borne encephalitis virus. J. Virol. 79, 15107– 15113 (2005). 10.1128/JVI.79.24.15107-15113.2005 16306582 PMC1316042 source
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenNo blinding was used throughout all studies.
“No blinding was used throughout all studies.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationreasoningThe prolonged increase in serum antibody titers through day 42 and plateauing through at least day 70 in pigtail macaques is most likely due to sustained antigen expression mediated by repRNA, which may result in plasma cell activation akin to traditional vaccine booster immunizations.
“This is most likely due to the sustained antigen expression mediated by repRNA, which may result in plasma cell activation akin to what happens following traditional vaccine booster immunizations.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown dataBecause the 250 μg dose was administered concurrently to five injection sites in pigtail macaques, it cannot be ruled out that immunogenicity and safety measures would be different following administration of this dose via a single bolus injection.
“However, because the 250 μg dose was administered concurrently to five injection sites in the pigtail macaques, it cannot be ruled out that immunogenicity and safety measures would be different to those following administration of this dose via a single bolus injection.”
Quote in the paperNot a substantial claimMay combine two claims.
Study design and conductreasoningThese conclusions are drawn in the absence of challenge data and from a limited number of animals and at time points after vaccination where observed responses, especially T-cell responses, exhibited great variability.
“However, these conclusions are drawn in the absence of challenge data and from a limited number of animals and at time points after vaccination where observed responses, especially T-cell responses, exhibited great variability.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenMouse group sizes were based on power analyses using data from previous experiments using a similar repRNA platform and mice were randomly distributed between groups.
“Mouse group sizes were based on power analyses using data from previous experiments using a similar repRNA platform and mice were randomly distributed between groups.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenFive pigtail macaques were stratified based on age and weight.
“Five pigtail macaques were stratified based on age and weight.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Pigtail macaques more closely resemble humans in the immune response to vaccination than mice do.
“nonhuman primate model that more closely resembles humans in the immune response to vaccination”
The paper relies on this without support.
Immune responses and protection observed in mice and pigtail macaques are predictive of protective immunity in humans.
“Together, our results support further development of LION/repRNA-CoV2S as a vaccine candidate for protection against COVID-19.”
Cites
A new coronavirus associated with human respiratory disease in China
Wu, F., Zhao, S., Yu, B., Chen, Y.-M., Wang, W., Song, Z.-G., Hu, Y., Tao, Z.-W., Tian, J.-H., Pei, Y.-Y., et al. (2020) · Nature · doi:10.1038/s41586-020-2008-3 · Cited by 11,688 · see citing works
Structure, function and antigenicity of the SARS-CoV-2 spike glycoprotein
Walls, A. C., Park, Y.-J., Tortorici, M. A., Wall, A., McGuire, A. T., & Veesler, D. (2020) · doi:10.1101/2020.02.19.956581 · Cited by 8,586 · see citing works
Self-citationA novel coronavirus outbreak of global health concern
Wang, C., Horby, P. W., Hayden, F. G., & Gao, G. F. (2020) · The Lancet · doi:10.1016/s0140-6736(20)30185-9 · Cited by 7,700 · see citing works
Hamming, I., Timens, W., Bulthuis, M., Lely, A., Navis, G., & van Goor, H. (2004) · The Journal of Pathology · doi:10.1002/path.1570 · Cited by 5,676 · see citing works
Grifoni, A., Weiskopf, D., Ramirez, S. I., Mateus, J., Dan, J. M., Moderbacher, C. R., Rawlings, S. A., Sutherland, A., Premkumar, L., Jadi, R. S., et al. (2020) · Cell · doi:10.1016/j.cell.2020.05.015 · Cited by 3,595 · see citing works
Outbreak of pneumonia of unknown etiology in Wuhan, China: The mystery and the miracle
Lu, H., Stratton, C. W., & Tang, Y. (2020) · Journal of Medical Virology · doi:10.1002/jmv.25678 · Cited by 3,497 · see citing works
M-1/M-2 Macrophages and the Th1/Th2 Paradigm
Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J., & Hill, A. M. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.12.6166 · Cited by 3,287 · see citing works
Letko, M., Marzi, A., & Munster, V. (2020) · Nature Microbiology · doi:10.1038/s41564-020-0688-y · Cited by 3,109 · see citing works
The alphaviruses: gene expression, replication, and evolution.
Strauss, J. H., & Strauss, E. G. (1994) · Microbiological Reviews · doi:10.1128/mmbr.58.3.491-562.1994 · Cited by 2,221 · cited 1× · see citing works
“quire only a single administration to be effective (30), they offer considerable potential to meet this need.”
BackgroundThe COVID-19 vaccine development landscape
Le, T. T., Andreadakis, Z., Kumar, A., Román, R. G., Tollefsen, S., Saville, M. K., & Mayhew, S. (2020) · Nature Reviews Drug Discovery · doi:10.1038/d41573-020-00073-5 · Cited by 1,959 · see citing works
Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody
Pinto, D., Park, Y.-J., Beltramello, M., Walls, A. C., Tortorici, M. A., Bianchi, S., Jaconi, S., Culap, K., Zatta, F., De Marco, A., et al. (2020) · Nature · doi:10.1038/s41586-020-2349-y · Cited by 1,885 · see citing works
Self-citationStructural and functional analysis of a potent sarbecovirus neutralizing antibody
Pinto, D., Park, Y.-J., Beltramello, M., Walls, A. C., Tortorici, M. A., Bianchi, S., Jaconi, S., Culap, K., Zatta, F., De Marco, A., et al. (2020) · doi:10.1101/2020.04.07.023903 · Cited by 1,752 · see citing works
Self-citationThe spike protein of SARS-CoV — a target for vaccine and therapeutic development
Du, L., He, Y., Zhou, Y., Liu, S., Zheng, B.-J., & Jiang, S. (2009) · Nature Reviews Microbiology · doi:10.1038/nrmicro2090 · Cited by 1,665 · see citing works
Zanganeh, S., Hutter, G., Spitler, R., Lenkov, O., Mahmoudi, M., Shaw, A., Pajarinen, J. S., Nejadnik, H., Goodman, S., Moseley, M., et al. (2016) · Nature Nanotechnology · doi:10.1038/nnano.2016.168 · Cited by 1,647 · see citing works
Development of an inactivated vaccine candidate for SARS-CoV-2
Gao, Q., Bao, L., Mao, H., Wang, L., Xu, K., Yang, M., Li, Y., Zhu, L., Wang, N., Lv, Z., et al. (2020) · Science · doi:10.1126/science.abc1932 · Cited by 1,434 · see citing works
DNA vaccine protection against SARS-CoV-2 in rhesus macaques
Yu, J., Tostanoski, L. H., Peter, L., Mercado, N. B., McMahan, K., Mahrokhian, S. H., Nkolola, J. P., Liu, J., Li, Z., Chandrashekar, A., et al. (2020) · Science · doi:10.1126/science.abc6284 · Cited by 997 · see citing works
ChAdOx1 nCoV-19 vaccine prevents SARS-CoV-2 pneumonia in rhesus macaques
van Doremalen, N., Lambe, T., Spencer, A., Belij-Rammerstorfer, S., Purushotham, J. N., Port, J. R., Avanzato, V. A., Bushmaker, T., Flaxman, A., Ulaszewska, M., et al. (2020) · Nature · doi:10.1038/s41586-020-2608-y · Cited by 914 · see citing works
A New Generation of Animal Cell Expression Vectors Based on the Semliki Forest Virus Replicon
Liljeström, P., & Garoff, H. (1991) · Nature Biotechnology · doi:10.1038/nbt1291-1356 · Cited by 905 · see citing works
Traggiai, E., Becker, S., Subbarao, K., Kolesnikova, L., Uematsu, Y., Gismondo, M. R., Murphy, B. R., Rappuoli, R., & Lanzavecchia, A. (2004) · Nature Medicine · doi:10.1038/nm1080 · Cited by 697 · see citing works
Jensen, S., & Thomsen, A. R. (2012) · Journal of Virology · doi:10.1128/jvi.05738-11 · Cited by 604 · cited 1× · see citing works
“In addition, repRNA vaccines mimic an Alphavirus infection in which viral-sensing stress factors are triggered, and innate pathways are activated through Toll-like receptors and retinoic acid inducible gene I to produce interferons (IFNs), proinflammatory factors, and chemotaxis of antigen-presenting cells, as well as…”
BackgroundUnexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion
Walls, A. C., Xiong, X., Park, Y.-J., Tortorici, M. A., Snijder, J., Quispe, J., Cameroni, E., Gopal, R., Dai, M., Lanzavecchia, A., et al. (2019) · Cell · doi:10.1016/j.cell.2018.12.028 · Cited by 582 · see citing works
Self-citationTseng, C.-T. K., Sbrana, E., Iwata‐Yoshikawa, N., Newman, P. C., Garron, T. M., Atmar, R. L., Peters, C. J., & Couch, R. B. (2012) · PLoS ONE · doi:10.1371/journal.pone.0035421 · Cited by 555 · cited 2× · see citing works
“Given that severe, life-threatening COVID-19 appears to be more common among elderly individuals, irrespective of type of T helper cell response, and that severe SARS is associated with skewing toward TH2 antibody profiles with an inadequate TH1 response (16, 17, 43), the ability of LION/repRNA-CoV2S to induce strong…”
BackgroundT cell-mediated immune response to respiratory coronaviruses
Channappanavar, R., Zhao, J., & Perlman, S. (2014) · Immunologic Research · doi:10.1007/s12026-014-8534-z · Cited by 512 · see citing works
Vogel, A. B., Lambert, L., Kinnear, E., Busse, D., Erbar, S., Reuter, K. C., Wicke, L., Perkovic, M., Beissert, T., Haas, H., et al. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2017.11.017 · Cited by 501 · see citing works
Tang, F., Quan, Y., Xin, Z.-T., Wrammert, J., Ma, M.-J., Lv, H., Wang, T.-B., Yang, H., Richardus, J. H., Liu, W., et al. (2011) · The Journal of Immunology · doi:10.4049/jimmunol.0903490 · Cited by 496 · see citing works
Pushko, P., Parker, M., Ludwig, G. V., Davis, N., Johnston, R. E., & Smith, J. (1997) · Virology · doi:10.1006/viro.1997.8878 · Cited by 444 · see citing works
Memory T cell responses targeting the SARS coronavirus persist up to 11 years post-infection
Ng, O.-W., Chia, A., Tan, A. T., Jadi, R. S., Leong, H. N., Bertoletti, A., & Tan, Y.-J. (2016) · Vaccine · doi:10.1016/j.vaccine.2016.02.063 · Cited by 436 · see citing works
Lack of Reinfection in Rhesus Macaques Infected with SARS-CoV-2
Bao, L., Deng, W., Gao, H., Xiao, C., Liu, J., Xue, J., Lv, Q., Liu, J., Yu, P., Xu, Y., et al. (2020) · doi:10.1101/2020.03.13.990226 · Cited by 419 · see citing works
SARS-like WIV1-CoV poised for human emergence
Menachery, V. D., Yount, B. L., Sims, A. C., Debbink, K., Agnihothram, S. S., Gralinski, L. E., Graham, R. L., Scobey, T., Plante, J. A., Royal, S. R., et al. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1517719113 · Cited by 418 · see citing works
Channappanavar, R., Fett, C., Zhao, J., Meyerholz, D. K., & Perlman, S. (2014) · Journal of Virology · doi:10.1128/jvi.01505-14 · Cited by 411 · see citing works
Sindbis Virus: An Efficient, Broad Host Range Vector for Gene Expression in Animal Cells
Xiong, C., Levis, R., Shen, P., Schlesinger, S., Rice, C. M., & Huang, H. V. (1989) · Science · doi:10.1126/science.2922607 · Cited by 409 · see citing works
Sindbis virus expression vectors: packaging of RNA replicons by using defective helper RNAs
Bredenbeek, P. J., Frolov, I. V., Rice, C. M., & Schlesinger, S. (1993) · Journal of Virology · doi:10.1128/jvi.67.11.6439-6446.1993 · Cited by 367 · see citing works
Zhao, J., Zhao, J., & Perlman, S. (2010) · Journal of Virology · doi:10.1128/jvi.01049-10 · Cited by 340 · see citing works
The need for IgG2c specific antiserum when isotyping antibodies from C57BL/6 and NOD mice
Martin, R. M., Brady, J. L., & Lew, A. M. (1998) · Journal of Immunological Methods · doi:10.1016/s0022-1759(98)00015-5 · Cited by 330 · see citing works
The outbreak of SARS-CoV-2 pneumonia calls for viral vaccines
Shang, W., Yang, Y., Rao, Y., & Rao, X. (2020) · npj Vaccines · doi:10.1038/s41541-020-0170-0 · Cited by 275 · cited 1× · see citing works
“However, mRNA and DNA vaccines may not be able to induce protective efficacy in humans after a single immunization because, similar to inactivated and recombinant subunit protein vaccines, they typically require multiple administrations over an extended period of time to become effective (19).”
BackgroundChAdOx1 nCoV-19 vaccination prevents SARS-CoV-2 pneumonia in rhesus macaques
van Doremalen, N., Lambe, T., Spencer, A., Belij-Rammerstorfer, S., Purushotham, J. N., Port, J. R., Avanzato, V., Bushmaker, T., Flaxman, A., Ulaszewska, M., et al. (2020) · doi:10.1101/2020.05.13.093195 · Cited by 246 · see citing works
Alphavirus-based expression vectors: strategies and applications.
Frolov, I. V., Hoffman, T. A., Prágai, B. M., Dryga, S. A., Huang, H. V., Schlesinger, S., & Rice, C. M. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.21.11371 · Cited by 238 · see citing works
He, Y., Lü, H., Siddiqui, P., Zhou, Y., & Jiang, S. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.174.8.4908 · Cited by 237 · see citing works
Enhancing immune responses using suicidal DNA vaccines
Berglund, P., Smerdou, C., Fleeton, M. N., Tubulekas, L., & Liljeström, P. (1998) · Nature Biotechnology · doi:10.1038/nbt0698-562 · Cited by 229 · see citing works
Self-citationHigh-performance iron oxide nanoparticles for magnetic particle imaging – guided hyperthermia (hMPI)
Bauer, L. M., Situ, S. F., Griswold, M. A., & Samia, A. C. S. (2016) · Nanoscale · doi:10.1039/c6nr01877g · Cited by 221 · see citing works
Corti, D., Zhao, J., Pedotti, M., Simonelli, L., Agnihothram, S., Fett, C., Fernandez-Rodriguez, B., Foglierini, M., Agatic, G., Vanzetta, F., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1510199112 · Cited by 216 · see citing works
Jiang, S., He, Y., & Liu, S. (2005) · Emerging infectious diseases · doi:10.3201/1107.050219 · Cited by 215 · see citing works
Calabrό, S., Tritto, E., Pezzotti, A., Taccone, M., Muzzi, A., Bertholet, S., Gregorio, E. D., O’Hagan, D. T., Baudner, B. C., & Seubert, A. (2013) · Vaccine · doi:10.1016/j.vaccine.2013.05.007 · Cited by 215 · see citing works
Bernstein, D. I., Reap, E. A., Katen, K., Watson, A., Smith, K., Norberg, P., Olmsted, R. A., Hoeper, A., Morris, J., Negri, S., et al. (2009) · Vaccine · doi:10.1016/j.vaccine.2009.09.135 · Cited by 212 · see citing works
Kinney, R. M., Chang, G. J., Tsuchiya, K. R., Sneider, J. M., Roehrig, J. T., Woodward, T. M., & Trent, D. W. (1993) · Journal of Virology · doi:10.1128/jvi.67.3.1269-1277.1993 · Cited by 207 · see citing works
Honda‐Okubo, Y., Barnard, D. L., Ong, C. H., Peng, B., Tseng, C.-T. K., & Petrovsky, N. (2014) · Journal of Virology · doi:10.1128/jvi.02980-14 · Cited by 204 · see citing works
Self-replicating Semliki Forest virus RNA as recombinant vaccine
Zhou, X., Berglund, P., Rhodes, G., Parker, S. E., Jondal, M., & Liljeström, P. (1994) · Vaccine · doi:10.1016/0264-410x(94)90074-4 · Cited by 193 · see citing works
Self-citationKhandhar, A. P., Keselman, P., Kemp, S. J., Ferguson, R. M., Goodwill, P. W., Conolly, S., & Krishnan, K. M. (2016) · Nanoscale · doi:10.1039/c6nr08468k · Cited by 179 · see citing works
Self-citationIron Oxide Nanoparticles-Based Vaccine Delivery for Cancer Treatment
Zhao, Y., Zhao, X., Cheng, Y. G., et al. (2018) · Molecular Pharmaceutics · doi:10.1021/acs.molpharmaceut.7b01103 · Cited by 165 · see citing works
Yu, E. Y., Chandrasekharan, P., Berzon, R., Tay, Z. W., Zhou, X. Y., Khandhar, A. P., Ferguson, R. M., Kemp, S. J., Zheng, B., Goodwill, P. W., et al. (2017) · ACS Nano · doi:10.1021/acsnano.7b04844 · Cited by 161 · see citing works
Self-citationErasmus, J. H., Khandhar, A. P., Guderian, J., Granger, B., Archer, J., Archer, M., Gage, E., Fuerte-Stone, J., Larson, E., Lin, S., et al. (2018) · Molecular Therapy · doi:10.1016/j.ymthe.2018.07.010 · Cited by 161 · see citing works
Self-citationSelf-replicating alphavirus RNA vaccines
Ljungberg, K., & Liljeström, P. (2014) · Expert Review of Vaccines · doi:10.1586/14760584.2015.965690 · Cited by 137 · see citing works
Rockx, B., Corti, D., Donaldson, E., Sheahan, T., Stadler, K., Lanzavecchia, A., & Baric, R. (2008) · Journal of Virology · doi:10.1128/jvi.02377-07 · Cited by 134 · see citing works
Jiang, S., He, Y., & Liu, S. (2005) · Emerging infectious diseases · doi:10.3201/eid1107.050219 · Cited by 109 · see citing works
Aberle, J. H., Aberle, S. W., Kofler, R. M., & Mandl, C. W. (2005) · Journal of Virology · doi:10.1128/jvi.79.24.15107-15113.2005 · Cited by 91 · see citing works
Murine Leukemia Virus (MLV)-based Coronavirus Spike-pseudotyped Particle Production and Infection
Millet, J., & Whittaker, G. (2016) · BIO-PROTOCOL · doi:10.21769/bioprotoc.2035 · Cited by 91 · see citing works
Structural and functional analysis of a potent sarbecovirus neutralizing antibody
Pinto, D., Park, Y., Beltramello, M., Walls, A. C., Tortorici, M. A., Bianchi, S., Jaconi, S., Culap, K., Zatta, F., Marco, A. D., et al. (2020) · Worldwide Protein Data Bank · doi:10.2210/pdb6ws6/pdb · Cited by 84 · see citing works
Self-citationDesbien, A. L., Reed, J., Bailor, H. R., Cauwelaert, N. D., Laurance, J. D., Orr, M. T., Fox, C. B., Carter, D., Reed, S. G., & Duthie, M. S. (2014) · European Journal of Immunology · doi:10.1002/eji.201444543 · Cited by 78 · see citing works
Self-citationChen, H., Hou, J., Jiang, X., Ma, S., Meng, M., Wang, B., Zhang, M., Zhang, M., Tang, X., Zhang, F., et al. (2005) · The Journal of Immunology · doi:10.4049/jimmunol.175.1.591 · Cited by 75 · see citing works
Development and preclinical evaluation of an alphavirus replicon vaccine for influenza
Hubby, B., Talarico, T. L., Maughan, M. F., et al. (2007) · Vaccine · doi:10.1016/j.vaccine.2007.09.038 · Cited by 69 · see citing works
Self-citationReap, E. A., Morris, J., Dryga, S. A., et al. (2007) · Vaccine · doi:10.1016/j.vaccine.2007.08.016 · Cited by 62 · see citing works
Duthie, M. S., Hoeven, N. V., MacMillen, Z., et al. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02420 · Cited by 62 · see citing works
Self-citationDNA vaccine protection against SARS-CoV-2 in rhesus macaques
Ry, A. V., Ventura, J. D., Mercado, N. B., et al. (2020) · Carolina Digital Repository (University of North Carolina at Chapel Hill) · doi:10.17615/7ywj-4d04 · Cited by 56 · see citing works
Chaplin, J., Chappell, C. P., & Clark, E. A. (2013) · The Journal of Experimental Medicine · doi:10.1084/jem.20130188 · Cited by 40 · see citing works
Pseudoinfectious Venezuelan Equine Encephalitis Virus: a New Means of Alphavirus Attenuation
Atasheva, S., Kim, D., Akhrymuk, M., Morgan, D., Frolova, E., & Frolov, I. (2012) · Journal of Virology · doi:10.1128/jvi.02881-12 · Cited by 30 · see citing works
Munson, P. V., Liu, Y., Bratt, D., et al. (2018) · Human Vaccines & Immunotherapeutics · doi:10.1080/21645515.2018.1448328 · Cited by 27 · cited 2× · see citing works
“Macaque cell intracellular cytokine staining Multiparameter flow cytometry was used to determine T cell immune responses using peptide-stimulated PBMC as previously described (60).”
MethodSelf-citationKhandhar, A. P., Wilson, G. J., Kaul, M. G., Salamon, J., Jung, C., & Krishnan, K. M. (2018) · Journal of Biomedical Materials Research Part A · doi:10.1002/jbm.a.36438 · Cited by 20 · see citing works
Self-citationMorse, M. A., Hobeika, A. C., Gwin, W. R., et al. (2015) · Journal for ImmunoTherapy of Cancer · doi:10.1186/2051-1426-3-s2-p444 · Cited by 15 · see citing works
O’Connor, M. A., Munson, P. V., Tunggal, H. C., Hajari, N., Lewis, T. B., Bratt, D., Moats, C. R., Smedley, J. V., Bagley, K., Mullins, J. I., et al. (2018) · AIDS Research and Human Retroviruses · doi:10.1089/aid.2018.0184 · Cited by 13 · see citing works
Self-citationThe 5th virus-like particle and nano-particle vaccines (VLPNPV) conference
Engeroff, P., & Bachmann, M. F. (2018) · Expert Review of Vaccines · doi:10.1080/14760584.2019.1557522 · Cited by 12 · see citing works
Flagged first, then by citations
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Lipid nanoparticles for mRNA delivery
Hou, X., Zaks, T., Langer, R., & Dong, Y. (2021) · Nature Reviews Materials · doi:10.1038/s41578-021-00358-0 · Cited by 4,076 · see citing works
mRNA-lipid nanoparticle COVID-19 vaccines: structure and stability
Schoenmaker, L., Witzigmann, D., Kulkarni, J. A., Verbeke, R., Kersten, G., Jiskoot, W., & Crommelin, D. J. A. (2021) · International Journal of Pharmaceutics · doi:10.1016/j.ijpharm.2021.120586 · Cited by 1,566 · see citing works
“Because of their replication competence, the injected dose for SAM vaccines is lower than for conventional mRNA vaccines and one dose might be sufficient for protection (Erasmus et al., 2020; Vogel et al., 2018).”
N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2
McCallum, M., De Marco, A., Lempp, F. A., Tortorici, M. A., Pinto, D., Walls, A. C., Beltramello, M., Chen, A., Liu, Z., Zatta, F., et al. (2021) · Cell · doi:10.1016/j.cell.2021.03.028 · Cited by 901 · see citing works
Self-citationWalls, A. C., Fiala, B., Schäfer, A., Wrenn, S., Pham, M. N., Murphy, M., Tse, L. V., Shehata, L., O’Connor, M. A., Chen, C., et al. (2020) · Cell · doi:10.1016/j.cell.2020.10.043 · Cited by 532 · see citing works
“At each study timepoint, full physical exams and evaluation of general health were performed on the animals, as previously described (Erasmus et al., 2020), and no adverse events were observed.”
Self-citationAdvances in COVID-19 mRNA vaccine development
Fang, E., Liu, X., Li, M., Zhang, Z., Song, L., Zhu, B., Wu, X., Liu, J., Zhao, D., & Li, Y. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-00950-y · Cited by 601 · see citing works
“Preclinical results indicate that this delivery vehicle can improve vaccine stability, delivery efficiency and immunogenicity, thereby inducing strong neutralizing antibodies and T cell response in mice and non-human primates.(338)”
BackgroundHuang, Y., Guo, X., Wu, Y., Chen, X., Feng, L., Xie, N., & Shen, G. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01745-z · Cited by 528 · see citing works
mRNA vaccine: a potential therapeutic strategy
Wang, Y., Zhang, Z., Luo, J., Han, X., Wei, Y., & Wei, X. (2021) · Molecular Cancer · doi:10.1186/s12943-021-01311-z · Cited by 422 · see citing works
Ma, X.-C., Zou, F., Yu, F., Li, R., Yuan, Y., Zhang, Y., Zhang, X., Deng, J., Chen, T., Song, Z., et al. (2020) · Immunity · doi:10.1016/j.immuni.2020.11.015 · Cited by 325 · see citing works
“mRNA vaccines, which include two candidates in phase III clinical evaluation, are also very easy to produce and havebeen found toprevent SARS-CoV-2 infection effectively (Erasmus et al., 2020; Jackson et al., 2020; Laczkó et al., 2020; Zhang et al., 2020a).”
BackgroundCOVID-19 mRNA vaccines: Platforms and current developments
Szabó, G. T., Mahiny, A. J., & Vlatkovic, I. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.02.016 · Cited by 308 · see citing works
“In the preclinical setting, the p-b regimen has been shown to induce a more potent T cell response in comparison with the administration of a single dose; 166 however, in the ongoing clinical trial, a one-shot regimen is also being tested.”
An Update on Self-Amplifying mRNA Vaccine Development
Blakney, A. K., Ip, S., & Geall, A. J. (2021) · Vaccines · doi:10.3390/vaccines9020097 · Cited by 288 · see citing works
Conn, V. M., Chinnaiyan, A. M., & Conn, S. J. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-024-00721-7 · Cited by 278 · see citing works
“Techniques such as self-transcribing circRNAs and amplifying circRNA replicons, similar to those used for linear RNA vaccines 204–206 , offer potential for achieving these goals.”
McDonald, I., Murray, S. M., Reynolds, C. J., Altmann, D. M., & Boyton, R. J. (2021) · npj Vaccines · doi:10.1038/s41541-021-00336-1 · Cited by 247 · see citing works
mRNA vaccines for infectious diseases — advances, challenges and opportunities
Pardi, N., & Krammer, F. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01042-y · Cited by 246 · see citing works
The Global Epidemic of the SARS-CoV-2 Delta Variant, Key Spike Mutations and Immune Escape
Tian, D., Sun, Y., Zhou, J., & Ye, Q. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.751778 · Cited by 192 · see citing works
“A prime/boost regimen induced potent T cell responses in mice, including antigen-specific responses in the lung and spleen (73).”
BackgroundImprinted SARS-CoV-2-Specific Memory Lymphocytes Define Hybrid Immunity
Rodda, L. B., Morawski, P. A., Pruner, K. B., Fahning, M. L., Howard, C. A., Franko, N., Logue, J. K., Eggenberger, J., Stokes, C., Golez, I., et al. (2022) · Cell · doi:10.1016/j.cell.2022.03.018 · Cited by 191 · see citing works
“Plaque reduction neutralization test (PRNT) PRNT assays were performed as previously described (Erasmus et al., 2020).”
MethodSelf-citationDelivery Strategies for mRNA Vaccines
Ramachandran, S., Satapathy, S. R., & Dutta, T. (2022) · Pharmaceutical Medicine · doi:10.1007/s40290-021-00417-5 · Cited by 182 · see citing works
A single-dose live-attenuated YF17D-vectored SARS-CoV-2 vaccine candidate
Sánchez-Felipe, L., Vercruysse, T., Sharma, S., Ma, J., Lemmens, V., Looveren, D. V., Javarappa, M. P. A., Boudewijns, R., Malengier‐Devlies, B., Liesenborghs, L., et al. (2020) · Nature · doi:10.1038/s41586-020-3035-9 · Cited by 174 · see citing works
mRNA cancer vaccines: Advances, trends and challenges
He, Q., Gao, H., Tan, D., Zhang, H., & Wang, J. (2022) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2022.03.011 · Cited by 167 · see citing works
Nanotechnology-based mRNA vaccines
Chen, S., Huang, X., Xue, Y., Álvarez‐Benedicto, E., Shi, Y., Chen, W., Koo, S., Siegwart, D. J., Dong, Y., & Tao, W. (2023) · Nature Reviews Methods Primers · doi:10.1038/s43586-023-00246-7 · Cited by 172 · see citing works
Han, X., Alu, A., Liu, H., Shi, Y., Wei, X., Cai, L., & Wei, Y. (2022) · Bioactive Materials · doi:10.1016/j.bioactmat.2022.01.011 · Cited by 159 · see citing works
“oxide (Fe3O4) nanoparticles, which demonstrated robust antibody and cellular immune responses [111].”
BackgroundBlair, R. V., Vaccari, M., Doyle‐Meyers, L. A., Roy, C. J., Russell‐Lodrigue, K., Fahlberg, M. D., Monjure, C. J., Beddingfield, B. J., Plante, K. S., Plante, J. A., et al. (2020) · American Journal Of Pathology · doi:10.1016/j.ajpath.2020.10.016 · Cited by 132 · see citing works
“14, 7, 14, 21, and at necropsy.”
N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2
McCallum, M., Marco, A. D., Lempp, F., Tortorici, M. A., Pinto, D., Walls, A. C., Beltramello, M., Chen, A., Liu, Z., Zatta, F., et al. (2021) · doi:10.1101/2021.01.14.426475 · Cited by 901 · see citing works
Self-citationNanotechnology-empowered vaccine delivery for enhancing CD8+ T cells-mediated cellular immunity
Liu, G., Zhu, M., Zhao, X., & Nie, G. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.113889 · Cited by 114 · see citing works
mRNA vaccines for COVID-19 and diverse diseases
Hussain, A., Yang, H., Zhang, M., Liu, Q., Alotaibi, G., Irfan, M. F., He, H., Chang, J. K., Liang, X., Weng, Y., et al. (2022) · Journal of Controlled Release · doi:10.1016/j.jconrel.2022.03.032 · Cited by 117 · see citing works
Nanocarrier vaccines for SARS-CoV-2
Machhi, J., Shahjin, F., Das, S., Patel, M., Abdelmoaty, M. M., Cohen, J. D., Singh, P., Baldi, A., Bajwa, N., Kumar, R., et al. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.01.002 · Cited by 80 · see citing works
“repRNA-CoV2S should be further evaluated in clinical studies to confirm its immunogenicity in humans [309].”
Engineering nanoparticle toolkits for mRNA delivery
Sun, B. F., Wu, W., Narasipura, E. A., Ma, Y., Yu, C., Fenton, O. S., & Song, H. (2023) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2023.115042 · Cited by 93 · see citing works
Maruggi, G., Mallett, C. P., Westerbeck, J. W., Chen, T., Lofano, G., Friedrich, K., Qu, L., Sun, J., McAuliffe, J., Kanitkar, A. P., et al. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.01.001 · Cited by 88 · see citing works
“10,32,33 However, no information is available on the protective ef fi cacy of self-amplifying mRNA vaccines in an animal model manifesting some of the hallmarks of severe COVID-19 disease.”
Adjuvant physiochemistry and advanced nanotechnology for vaccine development
Ren, H., Jia, W., Xie, Y., Yu, M., & Chen, Y. (2023) · Chemical Society Reviews · doi:10.1039/d2cs00848c · Cited by 88 · see citing works
A self-amplifying RNA vaccine against COVID-19 with long-term room-temperature stability
Voigt, E. A., Gerhardt, A., Hanson, D., Jennewein, M. F., Battisti, P., Reed, S., Singh, J., Mohamath, R., Bakken, J., Beaver, S., et al. (2022) · npj Vaccines · doi:10.1038/s41541-022-00549-y · Cited by 89 · see citing works
Self-citationLi, X., Qi, J., Wang, J., Hu, W., Zhou, W., Wang, Y., & Li, T. (2024) · Theranostics · doi:10.7150/thno.84291 · Cited by 96 · see citing works
“Erasmus et al. [85] applied lipid inorganic nanoparticles (LIONs) to deliver replicon RNA (repRNA) encoding SARS-CoV-2 S protein to enhance vaccine stability, delivery, and immunogenicity.”
BackgroundA new generation of vaccines based on alphavirus self-amplifying RNA
Ballesteros-Briones, M. C., Silva-Pilipich, N., Herrador, G., Vanrell, L., & Smerdou, C. (2020) · Current Opinion in Virology · doi:10.1016/j.coviro.2020.08.003 · Cited by 87 · see citing works
Rise of the RNA machines – self-amplification in mRNA vaccine design
Comes, J. D. G., Pijlman, G. P., & Hick, T. A. H. (2023) · Trends in Biotechnology · doi:10.1016/j.tibtech.2023.05.007 · Cited by 87 · see citing works
A single-dose mRNA vaccine provides a long-term protection for hACE2 transgenic mice from SARS-CoV-2
Huang, Q., Ji, K., Tian, S., Wang, F., Huang, B., Tong, Z., Tan, S., Hao, J., Wang, Q., Tan, W., et al. (2021) · Nature Communications · doi:10.1038/s41467-021-21037-2 · Cited by 76 · see citing works
Self-Amplifying RNA Vaccine Candidates: Alternative Platforms for mRNA Vaccine Development
Schmidt, C., & Schnierle, B. S. (2023) · Pathogens · doi:10.3390/pathogens12010138 · Cited by 78 · see citing works
Self-Amplifying RNA Approach for Protein Replacement Therapy
Papukashvili, D., Rcheulishvili, N., Liu, C., Ji, Y., He, Y., & Wang, P. G. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232112884 · Cited by 76 · see citing works
“These delivery systems include chitosan nanogel alginate (Chitosan NGA) [112], dendrimer [113], or modified dendrimer nanoparticle (MDNP) [113,114], cell-penetrating peptides (CPP) PEI [115], cationic lipids [116], polyplexes [117], natural lipopolyplexes [118], NLC [119], lipid inorganic nanoparticle emulsion (LION e…”
BackgroundMethodPotential immuno-nanomedicine strategies to fight COVID-19 like pulmonary infections
Bonam, S. R., Kotla, N. G., Bohara, R. A., Rochev, Y. A., Webster, T. J., & Bayry, J. (2020) · Nano Today · doi:10.1016/j.nantod.2020.101051 · Cited by 76 · see citing works
mRNA vaccines: Past, present, future
Karam, M., & Daoud, G. (2022) · Asian Journal of Pharmaceutical Sciences · doi:10.1016/j.ajps.2022.05.003 · Cited by 74 · see citing works
Xiang, Q., Li, L., Wu, J., Tian, M., & Fu, Y. (2022) · Microbiological Research · doi:10.1016/j.micres.2022.126993 · Cited by 74 · see citing works
Nanomaterials for mRNA ‐based therapeutics: Challenges and opportunities
Li, D., Liu, Q., Yang, M., Xu, H., Zhu, M., Zhang, Y., Xu, J., Tian, C., Yao, J., Wang, L., et al. (2023) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10492 · Cited by 71 · see citing works
Liu, R., Americo, J. L., Cotter, C. A., Earl, P. L., Noam Erez, A., Peng, C., & Moss, B. (2021) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2026785118 · Cited by 66 · see citing works
“Other candidate CoV-2 vaccines, including ones based on vesicular stomatitis virus (15), an alphavirus-derived replicon RNA (16), an inactivated recombinant New-castle Disease virus (17), and modified VACV Ankara (MVA) (18, 19) are at early stages of evaluation.”
Wang, Z., Cui, K., Costabel, U., & Zhang, X. (2022) · Exploration · doi:10.1002/exp.20210082 · Cited by 66 · see citing works
An RNA-Based Vaccine Platform for Use against Mycobacterium tuberculosis
Larsen, S. E., Erasmus, J. H., Reese, V. A., Pecor, T., Archer, J., Kandahar, A., Hsu, F.-C., Nicholes, K., Reed, S. G., Baldwin, S. L., et al. (2023) · Vaccines · doi:10.3390/vaccines11010130 · Cited by 66 · see citing works
“For example, here we evaluated a prime/boost spaced 3 weeks apart in our ULDA challenge and have more recently established that 4–8 weeks between prime and boost drives better immune responses in regimens that include the repRNA platform (unpublished and [50]).”
BackgroundMethodInfluentialSelf-citationSARS-CoV-2 ORF9c Is a Membrane-Associated Protein that Suppresses Antiviral Responses in CellsPreprint
Andres, A. D., Feng, Y., Campos, A. R., Yin, J., Yang, C.-C., James, B. P., Murad, R., Kim, H., Deshpande, A. J., Gordon, D. E., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.08.18.256776 · Cited by 63 · see citing works
“Various therapeutic and vaccine strategies target viral entry mechanisms, such as vaccines or antibodies targeting on the Spike (S) protein (13-16); others target viral replication or assembly”
BackgroundLeventhal, S. S., Meade-White, K. D., Rao, D., Haddock, E., Leung, J. M., Scott, D. P., Archer, J. F., Randall, S., Erasmus, J. H., Feldmann, H., et al. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.104188 · Cited by 65 · see citing works
Self-citationPrasad, M., Kumar, R., Buragohain, L., Kumari, A., & Ghosh, M. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.696668 · Cited by 62 · see citing works
Liu, Y., Wu, Y., Luo, Z. Y., & Li, M. (2023) · iScience · doi:10.1016/j.isci.2023.106279 · Cited by 63 · see citing works
Nanomedicine strategies to target coronavirus
Heinrich, M. A., Martina, B. E. E., & Prakash, J. (2020) · Nano Today · doi:10.1016/j.nantod.2020.100961 · Cited by 59 · see citing works
Clinical development of therapeutic mRNA applications
Żak, M. M., & Zangi, L. (2025) · Molecular Therapy · doi:10.1016/j.ymthe.2025.03.034 · Cited by 62 · see citing works
Global SNP analysis of 11,183 SARS‐CoV‐2 strains reveals high genetic diversity
Yuan, F., Wang, L., Fāng, Y., & Wang, L. (2020) · Transboundary and Emerging Diseases · doi:10.1111/tbed.13931 · Cited by 57 · see citing works
Self-Amplifying RNA: A Second Revolution of mRNA Vaccines against COVID-19
Silva-Pilipich, N., Beloki, U., Salaberry, L., & Smerdou, C. (2024) · Vaccines · doi:10.3390/vaccines12030318 · Cited by 57 · see citing works
“Erasmus and colleagues also developed a platform called LION (for Lipid InOrganic Nanoparticle), an emulsion aimed at enhancing vaccine stability, intracellular delivery, and immunogenicity [47].”
BackgroundMethodInfluentialNucleic Acid-Based Technologies Targeting Coronaviruses
Le, T. K., Paris, C., Khan, K. S., Robson, F., Ng, W., & Rocchi, P. (2020) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2020.11.010 · Cited by 57 · see citing works
“Recently, repRNA-CoV2S, a lipid inorganic nanoparticles-formulated, selfamplifying RNA vaccine encoding the SARS-CoV-2 S protein was reported to stimulate SARS-CoV-2 neutralizing antibody and T cell responses in mice and non-human primates [80].”
Cafferty, S. M., Haque, A. K. M. A., Vandierendonck, A., Weidensee, B., Plovyt, M., Stuchlíková, M., François, N., Valembois, S., Heyndríckx, L., Míchiels, J., et al. (2022) · Molecular Therapy · doi:10.1016/j.ymthe.2022.04.014 · Cited by 54 · see citing works
Clinical progress of nanomedicine-based RNA therapies
Lim, S. A., Cox, A., Tung, M., & Chung, E. J. (2021) · Bioactive Materials · doi:10.1016/j.bioactmat.2021.10.018 · Cited by 56 · see citing works
Kimura, T., Leal, J. M., Simpson, A., Warner, N. L., Berube, B. J., Archer, J. F., Park, S., Kurtz, R., Hinkley, T., Nicholes, K., et al. (2023) · Molecular Therapy · doi:10.1016/j.ymthe.2023.06.017 · Cited by 52 · see citing works
“11,54 In brief, the oil phase (squalene, Span 60, and DOTAP) was sonicated for 30 min in a 65 C water bath.”
Self-citationJain, S., Batra, H., Yadav, P., & Chand, S. (2020) · Vaccines · doi:10.3390/vaccines8040649 · Cited by 53 · see citing works
A lymph node–targeted Amphiphile vaccine induces potent cellular and humoral immunity to SARS-CoV-2
Steinbuck, M. P., Seenappa, L. M., Jakubowski, A., McNeil, L. K., Haqq, C. M., & DeMuth, P. C. (2021) · Science Advances · doi:10.1126/sciadv.abe5819 · Cited by 49 · see citing works
Böszörményi, K., Stammes, M., Fagrouch, Z. C., Kiemenyi-Kayere, G., Niphuis, H., Mortier, D., van Driel, N., Nieuwenhuis, I., Vervenne, R., Haaksma, T., et al. (2020) · Viruses · doi:10.3390/v13081673 · Cited by 47 · see citing works
“Many COVID-19 vaccines, among others those already authorized or approved for use in humans, have received their first efficacy evaluation in the rhesus macaque model [12, 36-45].”
BackgroundThe Importance of RNA-Based Vaccines in the Fight against COVID-19: An Overview
Machado, B. A. S., Hodel, K. V. S., Fonseca, L. M. D. S., Mascarenhas, L. A. B., Andrade, L. P. C. D. S., Rocha, V. P. C., Soares, M. B. P., Berglund, P., Duthie, M. S., Reed, S. G., et al. (2021) · Vaccines · doi:10.3390/vaccines9111345 · Cited by 52 · see citing works
Self-citationVaccine adjuvants for infectious disease in the clinic
Goetz, M. J., Thotathil, N., Zhao, Z., & Mitragotri, S. (2024) · Bioengineering & Translational Medicine · doi:10.1002/btm2.10663 · Cited by 56 · see citing works
“78”
Modulating intracellular pathways to improve non-viral delivery of RNA therapeutics
de Vyver, T. V., Smedt, S. C. D., & Raemdonck, K. (2021) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2021.114041 · Cited by 51 · see citing works
Mosaic sarbecovirus nanoparticles elicit cross-reactive responses in pre-vaccinated animals
Cohen, A. A., Keeffe, J. R., Schiepers, A., Dross, S., Greaney, A. J., Rorick, A. V., Gao, H., Gnanapragasam, P. N. P., Fan, C., West, A. P., et al. (2024) · Cell · doi:10.1016/j.cell.2024.07.052 · Cited by 51 · see citing works
“…either mosaic-8b or homo-typic SARS-2 RBD nanoparticles or with a bivalent RNA replicon vaccine formulated with Lipid InOrganic Nanoparticles (repRNA-LION 31 ) encoding the WA1 and the Omicron BA.1 spike proteins, which mimicked immunogens used in commercial bivalent mRNA-LNP vaccines (Figure 2A).”
Self-citationACTIVating Resources for the COVID-19 Pandemic: In Vivo Models for Vaccines and Therapeutics
Hewitt, J. A., Lutz, C., Florence, W. C., Pitt, M. L., Rao, S., Rappaport, J., & Haigwood, N. (2020) · Cell Host and Microbe · doi:10.1016/j.chom.2020.09.016 · Cited by 47 · see citing works
“Thus far, pigtail macaques have only been used for immunogenicity studies (Erasmus et al., 2020).”
Advances in the design and delivery of RNA vaccines for infectious diseases
Lokras, A. G., Bobak, T. R., Baghel, S. S., Sebastiani, F., & Foged, C. (2024) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2024.115419 · Cited by 50 · see citing works
Xu, K., Dai, L., & Gao, G. F. (2021) · International Immunology · doi:10.1093/intimm/dxab061 · Cited by 48 · see citing works
Viruses as tools in gene therapy, vaccine development, and cancer treatment
bin Umair, M., Fujimura, N. A., Kashif, H., Seerat-e-Fatima, Butt, F., Azhar, M., Munir, I., Ahmed, M. I., Khalil, W., Sharyar, H., et al. (2022) · Archives of Virology · doi:10.1007/s00705-022-05432-8 · Cited by 48 · see citing works
Engineered bacteria launch and control an oncolytic virus
Singer, Z. S., Pabón, J., Huang, H., Sun, W. Y., Luo, H., Grant, K. R., Obi, I., Coker, C., Rice, C. M., & Danino, T. (2025) · Nature Biomedical Engineering · doi:10.1038/s41551-025-01476-8 · Cited by 47 · see citing works
“In contrast, non-spreading viral RNAs generated through the deletion of structural proteins to yield ‘self-amplifying RNA’ have recently gained interest as a therapeutic medium 52 but still show limited persistence due to an inability to re-infect cells.”
Vaccines for COVID-19: A Systematic Review of Feasibility and Effectiveness
Mehraeen, E., Dadras, O., Afsahi, A. M., Karimi, A., MohsseniPour, M., Mirzapour, P., Barzegary, A., Behnezhad, F., Habibi, P., Salehi, M. A., et al. (2021) · Infectious Disorders - Drug Targets · doi:10.2174/1871526521666210923144837 · Cited by 45 · see citing works
Fc-mediated pan-sarbecovirus protection after alphavirus vector vaccination
Adams, L. E., Leist, S. R., Dinnon, K. H., West, A., Gully, K. L., Anderson, E. J., Loome, J. F., Madden, E. A., Powers, J. M., Schäfer, A., et al. (2023) · Cell Reports · doi:10.1016/j.celrep.2023.112326 · Cited by 45 · see citing works
“61 In the present study, we found that non-neutralizing antibodies can contribute to broad cross-vaccine protective immunity across clade 1a, 1b, and clade 2 sarbecoviruses, with as little as 75% amino acid identity be-tween spike protein sequences.”
Wørzner, K., Sheward, D. J., Schmidt, S., Hanke, L., Zimmermann, J., McInerney, G. M., Hedestam, G. B. K., Murrell, B., Christensen, D., & Pedersen, G. K. (2021) · EBioMedicine · doi:10.1016/j.ebiom.2020.103197 · Cited by 46 · see citing works
“Preliminary data also demonstrate high ef fi cacy for the RNA-and adenovirus vectored trimer proteins in clinical trials.”
InfluentialSelf-amplifying mRNA-Based Vaccine Technology and Its Mode of Action
Maruggi, G., Ulmer, J. B., Rappuoli, R., & Yu, D. L. (2021) · Current topics in microbiology and immunology · doi:10.1007/82_2021_233 · Cited by 45 · see citing works
Hawman, D. W., Meade-White, K. D., Clancy, C. S., Archer, J. F., Hinkley, T. C., Leventhal, S. S., Rao, D., Stamper, A., Lewis, M. C., Rosenke, R., et al. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.104196 · Cited by 43 · see citing works
Self-citationMaine, C. J., Miyake-Stoner, S. J., Spasova, D. S., Picarda, G. G. A., Chou, A. C., Brand, E. D., Olesiuk, M. D., Domingo, C. C., Little, H. J., Goodman, T. T., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-55843-9 · Cited by 52 · see citing works
“…this version of the VEEV-based vector has been clinically validated and advanced in a recently approved commercial vaccine 31 , no intentional design improvements have been made to the technology in over three decades that confer enhanced protein expression or vaccine immunogenicity 32 – 35 .”
IgM antibodies derived from memory B cells are potent cross-variant neutralizers of SARS-CoV-2
Hale, M. R., Netland, J., Chen, Y., Thouvenel, C. D., Smith, K. N., Rich, L. M., Vanderwall, E. R., Miranda, M. C., Eggenberger, J., Hao, L., et al. (2022) · The Journal of Experimental Medicine · doi:10.1084/jem.20220849 · Cited by 42 · see citing works
Self-citationState-of-the-Art of Nanodiagnostics and Nanotherapeutics against SARS-CoV-2
Derakhshan, M. A., Amani, A., & Majidi, R. F. (2021) · ACS Applied Materials & Interfaces · doi:10.1021/acsami.0c22381 · Cited by 42 · see citing works
Silva-Pilipich, N., Lasarte-Cía, A., Lozano, T., Martín-Otal, C., Lasarte, J. J., & Smerdou, C. (2022) · Molecular Therapy — Nucleic Acids · doi:10.1016/j.omtn.2022.07.020 · Cited by 41 · see citing works
“developed based on saRNA, which in preclinical studies have shown to elicit similar immune responses but at much lower doses.(49,50) This is probably due to the fact that saRNA can not only express higher antigen levels, but it can also elicit IFN type I responses and apoptosis, enhancing immune responses and allowing…”
Advances in vaccine delivery systems against viral infectious diseases
Kim, D., Wu, Y., Kim, Y. B., & Oh, Y. (2021) · Drug Delivery and Translational Research · doi:10.1007/s13346-021-00945-2 · Cited by 40 · see citing works
“In a nonhuman primate animal model, an inorganic nanoparticle-containing cationic squalene emulsion was investigated for intramuscular delivery of saRNA for the SARS-CoV-2 spike protein [63] (Fig.”
BackgroundMethodRecent advances in nanotechnology-based COVID-19 vaccines and therapeutic antibodies
Du, L., Yang, Y., Zhang, X., & Li, F. (2021) · Nanoscale · doi:10.1039/d1nr03831a · Cited by 41 · see citing works
Protection against SARS-CoV-2 transmission by a parenteral prime—Intranasal boost vaccine strategy
Christensen, D., Polacek, C., Sheward, D. J., et al. (2022) · EBioMedicine · doi:10.1016/j.ebiom.2022.104248 · Cited by 40 · see citing works
Komori, M., Nogimori, T., Morey, A. L., Sekida, T., Ishimoto, K., Hassett, M. R., Masuta, Y., Ode, H., Tamura, T., Suzuki, R., et al. (2023) · Nature Communications · doi:10.1038/s41467-023-38457-x · Cited by 37 · see citing works
In Vitro Transcribed RNA-Based Platform Vaccines: Past, Present, and Future
Perenkov, A. D., Sergeeva, A. D., Vedunova, M. V., & Krysko, D. V. (2023) · Vaccines · doi:10.3390/vaccines11101600 · Cited by 40 · see citing works
Mukhopadhyay, L., Yadav, P. D., Gupta, N., Mohandas, S., Patil, D. Y., Shete-Aich, A., Panda, S., & Bhargava, B. (2021) · The Indian Journal of Medical Research · doi:10.4103/ijmr.ijmr_4431_20 · Cited by 33 · see citing works
Langereis, M. A., Albulescu, I. C., Stammen‐Vogelzangs, J., Lambregts, M., Stachura, K., Miller, S., Bosco‐Lauth, A. M., Hartwig, A. E., Porter, S. M., Allen, M. H., et al. (2021) · npj Vaccines · doi:10.1038/s41541-021-00390-9 · Cited by 34 · see citing works
Wang, J., Zhang, Q., Ai, J., Liu, D., Liu, C., Xiang, H., Gu, Y., Guo, Y., Lv, J., Huang, Y., et al. (2022) · Hepatology International · doi:10.1007/s12072-022-10332-9 · Cited by 30 · see citing works
Hawman, D. W., Meade-White, K., Archer, J. F., Leventhal, S. S., Wilson, D., Shaia, C., Randall, S., Khandhar, A. P., Krieger, K., Hsiang, T.-Y., et al. (2022) · eLife · doi:10.7554/elife.75537 · Cited by 34 · see citing works
Self-citationCui, X., Vervaeke, P., Gao, Y., Opsomer, L., Sun, Q., Snoeck, J., Devriendt, B., Zhong, Z., & Sanders, N. N. (2024) · npj Vaccines · doi:10.1038/s41541-024-00932-x · Cited by 33 · see citing works
“Furthermore, sa-mRNA vaccines hold promise in conferring suf fi cient protection following a single-dose administration 15 .”
Larsen, S. E., Berube, B. J., Pecor, T., Cross, E., Brown, B. P., Williams, B. D., Johnson, E., Qu, P., Carter, L. P., Wrenn, S. P., et al. (2021) · Journal of Immunological Methods · doi:10.1016/j.jim.2021.113160 · Cited by 31 · see citing works
Lipid-Based Delivery Systems in Development of Genetic and Subunit Vaccines
Bolhassani, A. (2022) · Molecular Biotechnology · doi:10.1007/s12033-022-00624-8 · Cited by 35 · see citing works
Nie, Y., Shi, L. D., Zhang, Y., Guo, Y., & Gu, H. (2022) · Cancers · doi:10.3390/cancers14205107 · Cited by 32 · see citing works
“An RNA vaccine designed for COVID-19 also used iron oxide to enhance vaccine stability and immunogenicity [41,42], indicating that iron oxide-based nanovaccines might combine adjuvant effects with carrier function and could enter clinical application in the future if their efficacy and safety are of satisfaction.”
BackgroundImmunological perspectives on the pathogenesis, diagnosis, prevention and treatment of COVID-19
Ni, Y., Alu, A., Hong, L., Wang, Y., Wu, M., & Wei, X. (2021) · Molecular Biomedicine · doi:10.1186/s43556-020-00015-y · Cited by 31 · see citing works
“This vaccine candidate will enter clinical trials under the name HDT-301 [152].”
BackgroundAntibodies targeting the Crimean-Congo Hemorrhagic Fever Virus nucleoprotein protect via TRIM21
Leventhal, S. S., Bisom, T. C., Clift, D., Rao, D., Meade-White, K. D., Shaia, C., Murray, J., Mihalakakos, E. A., Hinkley, T. C., Reynolds, S. J., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-53362-7 · Cited by 31 · see citing works
Self-citationThe role and uses of antibodies in COVID-19 infections: a living review
Scourfield, D. O., Reed, S. G., Quastel, M. N., Alderson, J., Bart, V. M. T., Crespo, A. T., Jones, R., Pring, E., Richter, F., & Burnell, S. E. A. (2021) · Oxford Open Immunology · doi:10.1093/oxfimm/iqab003 · Cited by 30 · see citing works
Self-citationRecent Advances in Delivery Systems for Genetic and Other Novel Vaccines
Huang, S., Zhu, Y., Zhang, L., & Zhang, Z. (2021) · Advanced Materials · doi:10.1002/adma.202107946 · Cited by 28 · see citing works
Cao, M., Su, X., & Jiang, S. (2021) · Stem Cell Reports · doi:10.1016/j.stemcr.2020.12.010 · Cited by 27 · see citing works
Advances in saRNA Vaccine Research against Emerging/Re-Emerging Viruses
Liu, Y., Li, Y., & Hu, Q. (2023) · Vaccines · doi:10.3390/vaccines11071142 · Cited by 27 · see citing works
“To meet the global demand and to combat the emergence of new SARSCoV-2 variants, more saRNA vaccines have been developed and assessed in mice [9,82–85], hamsters [81,82], non-human primates [84,85], and humans [62,79,80].”
BackgroundDNA-launched RNA replicon vaccines induce potent anti-SARS-CoV-2 immune responses in mice
Szurgot, I., Hanke, L., Sheward, D., Vidakovics, L. P., Murrell, B., Mcinerney, G., & Liljeström, P. (2021) · Scientific Reports · doi:10.1038/s41598-021-82498-5 · Cited by 24 · see citing works
Trans-Amplifying RNA: A Journey from Alphavirus Research to Future Vaccines
Yıldız, A., Răileanu, C., & Beißert, T. (2024) · Viruses · doi:10.3390/v16040503 · Cited by 27 · see citing works
“Unfortunately, it was found that saRNA loses its function when modified by N1m Ψ [81].”
BackgroundOverview of Nonhuman Primate Models of SARS-CoV-2.
Trichel, A. (2021) · Comparative medicine · doi:10.30802/aalas-cm-20-000119 · Cited by 24 · see citing works
Development of an LNP-Encapsulated mRNA-RBD Vaccine against SARS-CoV-2 and Its Variants
Liu, C., Rcheulishvili, N., Shen, Z., Papukashvili, D., Xie, F., Wang, Z., Wang, X., He, Y., & Wang, P. G. (2022) · Pharmaceutics · doi:10.3390/pharmaceutics14051101 · Cited by 26 · see citing works
A self-amplifying RNA vaccine prevents enterovirus D68 infection and disease in preclinical models
Warner, N. L., Archer, J. F., Park, S., Singh, G., McFadden, K. M., Kimura, T., Nicholes, K., Simpson, A., Kaelber, J. T., Hawman, D. W., et al. (2024) · Science Translational Medicine · doi:10.1126/scitranslmed.adi1625 · Cited by 25 · see citing works
“LION was prepared as previously described ( 25 , 71 ).”
BackgroundMethodInfluentialSelf-citationTuberculosis vaccines update: Is an RNA-based vaccine feasible for tuberculosis?
Larsen, S. E., Baldwin, S. L., & Coler, R. N. (2023) · International Journal of Infectious Diseases · doi:10.1016/j.ijid.2023.03.035 · Cited by 25 · see citing works
- Authors
- Erasmus, J. H., Khandhar, A. P., O’Connor, M. A., Walls, A. C., Hemann, E. A., Murapa, P., Archer, J., Leventhal, S., Fuller, J. T., Lewis, T. B., Draves, K. E., Randall, S., Guerriero, K. A., Duthie, M. S., Carter, D., Reed, S. G., Hawman, D. W., Feldmann, H., Gale, M., Veesler, D., Berglund, P., & Fuller, D. H.
- Affiliations
- University of Washington (US)
- PAI Life Sciences (United States) (US)
- National Institute of Allergy and Infectious Diseases (US)
- HDT Bio, Seattle, WA 98102, USA.
- Corresponding author
- Fuller, Deborah Heydenburg
- ORCID
- Erasmus, Jesse H.
- Khandhar, Amit P.
- O’Connor, Megan A.
- Walls, Alexandra C.
- Hemann, Emily A.
- Murapa, Patience
- Archer, Jacob
- Fuller, James T.
- Lewis, Thomas B.
- Guerriero, Kathryn A.
- Duthie, Malcolm S.
- Carter, Darrick
- Reed, Steven G.
- Hawman, David W.
- Feldmann, Heinz
- Gale, Michael
- Veesler, David
- Berglund, Peter
- Fuller, Deborah Heydenburg
- Venue
- Science Translational Medicine
- Published
- 2020-08-05
- Volume
- 12
- Issue
- 555
- ISSN
- 1946-6234 (ISSN-L)
- 1946-6242
- PMC
- PMC7402629
- OpenAlex
- W3043351106
- Cited by
- 241
- References
- 69
- Citations by year
- 2026: 11 · 2025: 33 · 2024: 35 · 2023: 33 · 2022: 53 · 2021: 57 · 2020: 19
- FWCI
- 4.96
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Science Translational Medicine (publishedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- Funders
- National Institute of General Medical Sciences (R01GM120553)
- National Institute of Allergy and Infectious Diseases (P51OD010425, 27220140006C, 75N93019C00037, HHSN272201700059C, 1F32AI136371)
- Burroughs Wellcome Fund (Investigators in the pathogenesis of infectious disease award)
- Pew Charitable Trusts (Pew Biomedical Scholars Award)
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases
- University of Washington Center for Innate Immunity and Immune Disease
- Washington Research Foundation (WRF Postdoctoral Fellowship)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 detection and testing
- Keywords
- SARS-CoV-2, COVID-19 vaccines, spike protein, neutralizing antibodies, T cell response, prime-boost vaccination, aged mice, non-human primates, intramuscular injection
- MeSH terms
- Betacoronavirus, COVID-19, SARS-CoV-2, COVID-19 Vaccines, Alphavirus, Animals, Antibody Formation, Inorganic Chemicals, Lipids, Mice, Inbred BALB C, Mice, Inbred C57BL, Pneumonia, Viral, Primates, Replicon, RNA, Viral, T-Lymphocytes, Viral Vaccines, Coronavirus Infections, Mice, Nanoparticles, Antibodies, Neutralizing, Pandemics
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