Clade 2.3.4.4b but not historical clade 1 HA replicating RNA vaccine protects against bovine H5N1 challenge in mice
Open accessPublished version of a preprint
Abstract
The ongoing circulation of influenza A H5N1 in the United States has raised concerns of a pandemic caused by highly pathogenic avian influenza. Although the United States has stockpiled and is prepared to produce millions of vaccine doses to address an H5N1 pandemic, currently circulating H5N1 viruses contain multiple mutations within the immunodominant head domain of hemagglutinin (HA) compared to the antigens used in stockpiled vaccines. It is unclear if these stockpiled vaccines will need to be updated to match the contemporary H5N1 strains. Here we show that a replicating RNA vaccine expressing the HA of an H5N1 isolated from a US dairy cow confers complete protection against homologous lethal challenge in mice. A repRNA encoding the HA of a clade 1 H5 from 2004 (A/Vietnam/1203/2004) as utilized by some stockpiled vaccines, confers only partial protection. Our data highlight the utility of nucleic acid vaccines to be rapidly updated to match emergent viruses of concern while demonstrating that contemporary bovine H5N1 viruses can evade immunity elicited by historical HA antigens.
AI snapshot
Written from the paper’s full text.
TL;DR
A replicating RNA vaccine expressing the HA of contemporary bovine H5N1 fully protected mice against homologous lethal challenge, whereas a historical clade 1 Vietnam HA vaccine provided only partial protection. These data suggest circulating bovine H5N1 can evade immunity elicited by historical HA antigens and support rapid updating of nucleic acid vaccines.
Key findings
- A single intramuscular 10 µg dose of repHA-Bovine conferred complete protection against intranasal challenge with 100,000 TCID50 of A/bovine; sham-vaccinated mice all succumbed with a mean time to death (MTD) of 6.5 days, while 4/6 repHA-Vietnam mice succumbed with an MTD of 8.5 days and 2 showed no clinical disease. repNP-only mice succumbed similarly to sham controls.
- repHA-Bovine elicited virus neutralization (VN) titers of 1:30 against homologous A/bovine but no detectable neutralization against heterologous A/Vietnam; repHA-Vietnam elicited VN titers of 1:20 against homologous A/Vietnam but no detectable neutralization against A/bovine. Hemagglutination inhibition assays detected no neutralizing activity against either virus.
- Both repHA vaccines elicited HA-binding antibodies and HA-specific IFNγ ELISpot T-cell responses; repNP elicited NP-specific antibodies but no protection. The median lethal dose of A/bovine in C57BL6/J mice was <10 TCID50, indicating a stringent challenge.
- Bead-based binding assays showed repHA-Vietnam antibodies bound most H5 HAs but had reduced binding to A/bovine, whereas repHA-Bovine antibodies bound A/bovine strongly but had reduced binding to many other H5 clades; neither vaccine elicited antibodies binding clade 2.3.2.1 A/Hong Kong 2007 HA.
Methods
- Male and female C57BL6/J mice, 8 weeks old, were vaccinated once intramuscularly with a cumulative 10 µg of repRNA encoding A/Vietnam HA, A/bovine HA, A/bovine NP, or combinations; sham mice received irrelevant repRNA. Immunogenicity groups used n = 4 per group; challenge groups used n = 6 per group.
- Four weeks after vaccination, mice were challenged intranasally with 100,000 TCID50 of A/bovine/OH/B24OSU-342/2024 and monitored for weight loss and survival; separate LD50 studies used indicated virus doses.
- Main assays included ELISA for HA/NP binding antibodies, VN and HI neutralization assays, IFNγ ELISpot, and a Luminex bead-based multiplex HA-binding assay; statistical comparisons used GraphPad Prism v10.2.
Limitations
- The paper states that mice lacked pre-existing influenza immunity; C57BL6/J mice challenged with A/bovine develop severe neurological infection in addition to respiratory infection, so distinct correlates of protection may be required, and non-human primate studies are ongoing. It also states that actual stockpiled vaccines using distinct platforms were not evaluated, and that human A/Indonesia vaccine sera bound A/bovine HA but neutralizing capacity against A/bovine was not tested.
- Evident from the text: group sizes were small (n = 4 for immunogenicity, n = 6 for challenge), and neutralization assays used pooled sera (n = 4 per group) in duplicate, limiting assessment of individual variability. The study tested a single vaccine dose in mice without dose-ranging or boost regimens.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
12 of 16 cited sources checked · 10 supported · 0 flagged · accuracy not yet measured
- Premisecitation
The HA head domain is an immunodominant target of vaccine-induced immunity.
“the HA head is an immunodominant target of vaccine-induced immunity11”
- Also stated in: § Introduction · plain
“including in the HA10 an immunodominant target of vaccine-elicited immunity11”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [11] Ellebedy, A. H. et al. Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans. Proc. Natl. Acad. Sci. USA 111, 13133–13138 (2014). source
- Also stated in: § Introduction · plain
- Premisecitation
The repRNA/LIONTM platform is less reactogenic than traditional LNPs.
“The repRNA/LION™ platform is less reactogenic than traditional LNPs suggesting higher tolerable single vaccine doses would be possible33.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [33] Kimura, T. et al. A localizing nanocarrier formulation enables multi-target immune responses to multivalent replicating RNA with limited systemic inflammation. Mol. Ther. 31, 2360–2375 (2023). source
- Interpretationcitation
Pre-existing immunity to influenza may improve the breadth of responses elicited by H5 HA vaccines.
“These data support the hypothesis that pre-existing immunity to influenza may improve the breadth of responses elicited by H5 HA vaccines.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [11] Ellebedy, A. H. et al. Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans. Proc. Natl. Acad. Sci. USA 111, 13133–13138 (2014). source
- Interpretationcitation
Given the rarity of H9, H6 and H10 human infections, the binding antibodies likely represent heterosubtypic immunity elicited by vaccination or exposure to other influenza A subtypes.
“Given the rarity of H9, H6 and H10 human infections23–25 it is likely the binding antibodies represent heterosubtypic immunity elicited by vaccination or exposure to other influenza A subtypes.”
Quote in the paperNot a substantial claim3 of 3 sources checked- cites [23] Khan, S. U., Anderson, B. D., Heil, G. L., Liang, S. & Gray, G. C. A systematic review and meta-analysis of the seroprevalence of influenza A(H9N2) infection among humans. J. Infect. Dis. 212, 562–569 (2015). source
- cites [24] Qi, W. et al. Antibodies against H10N8 avian influenza virus among animal workers in Guangdong Province before November 30, 2013, when the first human H10N8 case was recognized. BMC Med. 12, 205 (2014). source
- cites [25] Huang, S. Y. et al. Serological comparison of antibodies to avian influenza viruses, subtypes H5N2, H6N1, H7N3 and H7N9 between poultry workers and non-poultry workers in Taiwan in 2012. Epidemiol. Infect. 143, 2965–2974 (2015). source
- Findingown data
The median lethal dose (LD50) of A/bovine in C57BL6/J mice is <10 TCID50s.
“Subsequent studies showed that the median lethal dose (LD50) of A/bovine in C57BL6/J mice is <10 TCID50s (Supplemental Fig. 4), indicating our challenge model represented a stringent challenge of vaccine efficacy.”
Quote in the paperSubstantial claim
- Findingown data
The HA of A/Vietnam and A/bovine are antigenically distinct.
“The HA of A/Vietnam and A/bovine are antigenically distinct”
- Also stated in: § Vaccine-encoded H5 HA antigens elicit antibodies with distinct binding to homosubtypic HAs · hedged
“These data are consistent with our ELISA data and suggest that repHA-Vietnam and repHA-Bovine elicit antibodies with distinct homosubtypic reactivity.”
Quote in the paperSubstantial claim - Also stated in: § Vaccine-encoded H5 HA antigens elicit antibodies with distinct binding to homosubtypic HAs · hedged
- Findingown data
Serum from mice vaccinated with either repHA-Vietnam or repHA-Bovine exhibited significant binding antibodies against both A/Vietnam and A/bovine HAs compared to sham-vaccinated mice.
“Compared to the sham-vaccinated group, serum from mice vaccinated with either repHA-Vietnam or repHA-Bovine exhibited significant binding antibodies against both HAs (Fig. 2a).”
Quote in the paperSubstantial claim - Findingown data
Most mutations between A/Vietnam and A/bovine HA are concentrated in the head domain of HA.
“This analysis highlighted that most mutations between A/Vietnam and A/bovine HA were concentrated in the head domain of HA (Fig. 1).”
Quote in the paperSubstantial claim - Findingown data
Most mice that survived clade 2.3.4.4b infection had antibodies that bound both A/Vietnam and A/bovine HA, like repHA-Bovine vaccinated mice.
“In contrast, most mice that survived clade 2.3.4.4b infection had antibodies that bound both A/Vietnam and A/bovine HA (Fig. 3c, d) like repHA-Bovine vaccinated mice.”
Quote in the paperNot a substantial claim - Findingown data
Both repHA-Vietnam and repHA-Bovine vaccination failed to elicit antibodies that bound clade 2.3.2.1 (A/Hong Kong 2007) HA.
“Interestingly, both repHA-Vietnam and repHA-Bovine vaccination failed to elicit antibodies that bound clade 2.3.2.1 (A/Hong Kong 2007) HA suggesting that neither vaccine would provide optimal immunity against this virus in mice.”
Quote in the paperSubstantial claim - Findingown data
A replicating RNA vaccine expressing the HA of an H5N1 isolated from a US dairy cow (A/bovine) confers complete protection against homologous lethal challenge in mice.
“Here we show that a replicating RNA vaccine expressing the HA of an H5N1 isolated from a US dairy cow confers complete protection against homologous lethal challenge in mice.”
- Also stated in: § repHA-Bovine vaccination protects against lethal A/bovine challenge · plain
“In contrast, mice vaccinated with the homologous repHA-Bovine or repHA + repNP were completely protected from clinical disease (Fig. 2e, f).”
- Also stated in: § Discussion · boosted
“Our data demonstrate that a single immunization with a repRNA expressing an HA from a contemporary H5N1 currently circulating within the United States confers complete protection against homologous lethal challenge in mice.”
Quote in the paperSubstantial claim - Also stated in: § repHA-Bovine vaccination protects against lethal A/bovine challenge · plain
- Findingown data
RepNP failed to elicit HA-specific T cells.
“Both repHA-Vietnam and repHA-Bovine elicited HA-specific T cells while repNP failed to elicit HA-specific T cells as expected (Fig. 2d).”
Quote in the paperNot a substantial claim - Findingown data
We observed significant differences in the binding profiles of antibodies elicited by each vaccination.
“We observed significant differences in the binding profiles of antibodies elicited by each vaccination (Fig. 3a).”
Quote in the paperSubstantial claim - Findingown data
RepHA-Vietnam vaccination elicited antibodies that had binding activity to most H5 HAs but with a notable reduction in binding to A/bovine.
“Overall, repHA-Vietnam vaccination elicited antibodies that had binding activity to most H5 HAs but with a notable reduction in binding to A/bovine (Fig. 3a, b).”
Quote in the paperSubstantial claim - Findingown data
One mouse that survived A/mink infection had antibodies that largely bound only A/bovine HA.
“However, one mouse that survived A/mink infection had antibodies that largely bound only A/bovine HA suggesting infection can elicit antibodies that largely fail to react to other H5 HAs (Fig. 3d).”
Quote in the paperNot a substantial claim - Findingown data
Binding antibodies elicited by repHA-Vietnam or repHA-Bovine were significantly reduced against the heterologous HA compared to the homologous HA.
“Interestingly, we observed significantly reduced binding antibodies against heterologous HAs (Fig. 2a) suggesting that the mutations between the A/Vietnam and A/bovine HAs (Fig. 1) can significantly reduce binding of antibodies elicited by heterologous vaccination.”
Quote in the paperSubstantial claim - Findingown data
Serum from repNP-only vaccinated animals had no detectable neutralizing activity.
“Serum from repNP-only vaccinated animals had no detectable neutralizing activity as expected (Fig. 2c).”
Quote in the paperNot a substantial claim - Findingown data
Sham-vaccinated mice all succumbed to A/bovine challenge with a mean time to death of 6.5 days.
“Sham-vaccinated mice all succumbed with a mean-time-to-death (MTD) of 6.5 days (Fig. 2e, f).”
Quote in the paperSubstantial claim - Findingown data
A repRNA encoding the HA of a clade 1 H5 from 2004 (A/Vietnam/1203/2004) as utilized by some stockpiled vaccines confers only partial protection against heterologous lethal A/bovine challenge in mice.
“A repRNA encoding the HA of a clade 1 H5 from 2004 (A/Vietnam/1203/2004) as utilized by some stockpiled vaccines, confers only partial protection.”
- Also stated in: § repHA-Bovine vaccination protects against lethal A/bovine challenge · hedged
“Surprisingly, four of six repHA-Vietnam mice also succumbed to the infection with a MTD of 8.5 days (Fig. 2e, f) while two mice exhibited no clinical disease following challenge (Fig. 2e, f), suggesting repHA-Vietnam provided incomplete protection against heterologous A/bovine challenge.”
- Also stated in: § Discussion · plain
“Surprisingly, heterologous protection was not observed in mice vaccinated with repHA-Vietnam suggesting bovine H5N1 can evade immunity elicited by historical HA antigens.”
Quote in the paperSubstantial claim - Also stated in: § repHA-Bovine vaccination protects against lethal A/bovine challenge · hedged
- Findingown data
Mice that survived A/Vietnam challenge had antibodies with reduced binding to A/bovine HA, like vaccinated mice.
“Mice that survived A/Vietnam challenge had antibodies with reduced binding to A/bovine HA, like vaccinated mice (Fig. 3c, d).”
Quote in the paperNot a substantial claim - Findingown data
Human vaccinee sera also reacted strongly to A/bovine HA similar to repHA-Bovine vaccinated mice.
“However, the human sera also reacted strongly to the A/bovine HA similar to our repHA-Bovine vaccinated mice (Fig. 3a) suggesting that pre-existing immunity, species-specific determinants, and/or the clade 2.1.3 HA utilized may improve the breadth of homosubtypic H5 HA reactivity.”
Quote in the paperNot a substantial claim - Findingown data
Mice vaccinated with homologous repHA-Bovine or repHA + repNP were completely protected from clinical disease after A/bovine challenge.
“In contrast, mice vaccinated with the homologous repHA-Bovine or repHA + repNP were completely protected from clinical disease (Fig. 2e, f).”
Quote in the paperSubstantial claim - Findingown data
Despite NP-specific antibody responses, repNP-only vaccinated mice succumbed with similar kinetics as sham-vaccinated mice.
“Despite NP-specific antibody responses in repNP-only vaccinated mice, these mice succumbed with similar kinetics as sham vaccinated mice (Fig. 2e, f), suggesting NP-specific responses were unable to protect against A/bovine challenge.”
Quote in the paperSubstantial claim - Findingown data
Neutralizing activity after a single immunization with repHA-Vietnam or repHA-Bovine is low or absent.
“These data suggest that while repHA-Vietnam and repHA-Bovine elicit HA-binding antibodies after a single immunization, neutralizing activity is low or absent, may be dose-dependent and the mutations between A/Vietnam and A/bovine can impact nAb binding and neutralization activity.”
Quote in the paperSubstantial claim - Findingown data
Using hemagglutination inhibition assay, no neutralizing activity against A/Vietnam or A/bovine was measured in vaccinated mice.
“Using this assay, we did not measure any neutralizing activity against A/Vietnam or A/bovine (Supplemental Fig. 3).”
Quote in the paperSubstantial claim - Findingown data
Many of the mutations between A/Vietnam and A/bovine HA mapped to footprints of previously characterized neutralizing antibodies FLUA-20, 2G1, and H5M9 that target three separate neutralizing epitopes in the HA.
“many of these mutations mapped to footprints of previously characterized neutralizing antibodies FLUA-2018, 2G119, and HM5920 that target three separate neutralizing epitopes in the HA (Fig. 1).”
Quote in the paperSubstantial claim - Findingown data
Mice that survived A/Vietnam, A/mountain lion or A/mink infection failed to produce antibodies that reacted to clade 2.3.2.1 HA.
“Similar to our results with sera from vaccinated mice (Fig. 3a, b), mice that survived A/Vietnam, A/mountain lion or A/mink infection failed to produce antibodies that reacted to clade 2.3.2.1 HA (Fig. 3d) suggesting unique determinants of immunity within this HA.”
Quote in the paperSubstantial claim - Findingown data
Mice that survived A/mink infection had antibodies that bound A/bovine HA as strongly as mice that survived A/mountain lion infection.
“Mice that survived A/mink infection, a clade 2.3.4.4b virus from 2022 had antibodies that bound A/bovine HA as strongly as mice that survived A/mountain lion infection, a clade 2.3.4.4b virus from 2024, suggesting that more recent clade 2.3.4.4b HA antigens such as A/Astrakhan may provide increased protection against A/bovine.”
Quote in the paperNot a substantial claim - Findingown data
Our evaluation of pooled human sera from individuals receiving an investigational H5 vaccine based on clade 2.1.3A/Indonesia/05/2005 PR8-IBCDC-RG221 showed broader H5 HA binding than vaccinated mice.
“Our evaluation of pooled human sera from individuals receiving an investigational H5 vaccine based on clade 2.1.3A/Indonesia/05/2005 PR8-IBCDC-RG221 showed broader H5 HA binding than vaccinated mice.”
Quote in the paperNot a substantial claim - Findingown data
Vaccination or infection of mice largely failed to elicit heterosubtypic binding antibodies, with sera from most animals having little-to-no reactivity to H3, H1, H6, or H10 HAs.
“Vaccination or infection of mice largely failed to elicit heterosubtypic binding antibodies with sera from most animals having little-to-no reactivity to H3, H1, H6, or H10 HAs (Supplemental Fig. 4).”
Quote in the paperNot a substantial claim - Findingown data
A single immunization with a repRNA expressing the homologous HA confers complete protection against stringent lethal A/bovine challenge in mice.
“Our data show that a single immunization with a repRNA expressing the homologous HA confers complete protection against stringent lethal A/bovine challenge in mice.”
Quote in the paperSubstantial claim - Findingreasoning
A historical HA, as utilized by some stockpiled vaccines, conferred only partial protection against A/bovine challenge in mice.
“In contrast, a historical HA, as utilized by some stockpiled vaccines, conferred only partial protection, likely due to mutations in the HA head domain.”
Quote in the paperSubstantial claim - Findingown data
Humans receiving an experimental vaccine based on the A/Indonesia HA had antibodies that bound to the A/bovine HA.
“our data showed that humans receiving an experimental vaccine based on the A/Indonesia HA had antibodies that bound to the A/bovine HA.”
Quote in the paperNot a substantial claim - Interpretationown data
Neutralizing activity after repHA-Vietnam or repHA-Bovine vaccination may be dose-dependent.
“These data suggest that while repHA-Vietnam and repHA-Bovine elicit HA-binding antibodies after a single immunization, neutralizing activity is low or absent, may be dose-dependent and the mutations between A/Vietnam and A/bovine can impact nAb binding and neutralization activity.”
Quote in the paperNot a substantial claim - Interpretationown data
The A/bovine challenge model represented a stringent challenge of vaccine efficacy.
“Subsequent studies showed that the median lethal dose (LD50) of A/bovine in C57BL6/J mice is <10 TCID50s (Supplemental Fig. 4), indicating our challenge model represented a stringent challenge of vaccine efficacy.”
Quote in the paperSubstantial claim - Interpretationown data
Neither repHA-Vietnam nor repHA-Bovine vaccine would provide optimal immunity against clade 2.3.2.1 (A/Hong Kong 2007) virus in mice.
“Interestingly, both repHA-Vietnam and repHA-Bovine vaccination failed to elicit antibodies that bound clade 2.3.2.1 (A/Hong Kong 2007) HA suggesting that neither vaccine would provide optimal immunity against this virus in mice.”
Quote in the paperSubstantial claim - Interpretationown data
NP-specific responses were unable to protect against A/bovine challenge.
“Despite NP-specific antibody responses in repNP-only vaccinated mice, these mice succumbed with similar kinetics as sham vaccinated mice (Fig. 2e, f), suggesting NP-specific responses were unable to protect against A/bovine challenge.”
Quote in the paperSubstantial claim - Interpretationown data
Contemporary bovine H5N1 viruses can evade immunity elicited by historical HA antigens.
“Our data highlight the utility of nucleic acid vaccines to be rapidly updated to match emergent viruses of concern while demonstrating that contemporary bovine H5N1 viruses can evade immunity elicited by historical HA antigens.”
- Also stated in: § Discussion · hedged
“Surprisingly, heterologous protection was not observed in mice vaccinated with repHA-Vietnam suggesting bovine H5N1 can evade immunity elicited by historical HA antigens.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · hedged
- Interpretationown data
The mutations between A/Vietnam and A/bovine can impact neutralizing antibody binding and neutralization activity.
“These data suggest that while repHA-Vietnam and repHA-Bovine elicit HA-binding antibodies after a single immunization, neutralizing activity is low or absent, may be dose-dependent and the mutations between A/Vietnam and A/bovine can impact nAb binding and neutralization activity.”
Quote in the paperSubstantial claim - Interpretationown data
RepHA-Vietnam and repHA-Bovine elicit antibodies with distinct homosubtypic reactivity.
“These data are consistent with our ELISA data and suggest that repHA-Vietnam and repHA-Bovine elicit antibodies with distinct homosubtypic reactivity.”
Quote in the paperSubstantial claim - Interpretationown data
The mutations between A/Vietnam and A/bovine HAs can significantly reduce binding of antibodies elicited by heterologous vaccination.
“Interestingly, we observed significantly reduced binding antibodies against heterologous HAs (Fig. 2a) suggesting that the mutations between the A/Vietnam and A/bovine HAs (Fig. 1) can significantly reduce binding of antibodies elicited by heterologous vaccination.”
Quote in the paperSubstantial claim - Study design and conductown data
Cells transfected with repRNAs encoding HA or NP confirmed appropriate high-level expression of both HA and NP.
“Cells transfected with these repRNAs confirmed appropriate high-level expression of both HA (Supplemental Fig. 1a, c) and NP (Supplemental Fig. 1b, c).”
Quote in the paperNot a substantial claim - Interpretationown data
Our results extend to immunity elicited by authentic viral infection.
“Our evaluation of sera from mice surviving H5N1 infection suggests our results extend to immunity elicited by authentic viral infection arguing against altered expression of HA by our repHA vaccines driving unique immunity.”
Quote in the paperNot a substantial claim - Interpretationown data
Protection against A/bovine challenge in repHA-Bovine vaccinated mice was associated with significant HA-binding antibodies that exhibited low-to-absent neutralizing activity against A/bovine.
“Protection was associated with significant HA-binding antibodies that exhibited low-to-absent neutralizing activity against A/bovine.”
Quote in the paperSubstantial claim - Premisecitation
C57BL6/J mice challenged with A/bovine develop a severe neurological infection in addition to respiratory infection.
“C57BL6/J mice challenged with A/bovine develop a severe neurological infection in addition to respiratory infection17.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Tipih, T. et al. Recent bovine HPAI H5N1 isolate is highly virulent for mice, rapidly causing acute pulmonary and neurologic disease. Preprint at bioRxiv https://doi.org/10.1101/2024.08.19.608652 (2024). source
- Interpretationown data
Our findings highlight the utility of nucleic acid-based vaccines such as the repRNA platform to enable rapid updating of vaccines to match emerging viral variants.
“In summary, our findings highlight the utility of nucleic acid-based vaccines such as the repRNA platform to enable rapid updating of vaccines to match emerging viral variants.”
Quote in the paperSubstantial claim - Interpretationown data
More recent clade 2.3.4.4b HA antigens such as A/Astrakhan may provide increased protection against A/bovine.
“Mice that survived A/mink infection, a clade 2.3.4.4b virus from 2022 had antibodies that bound A/bovine HA as strongly as mice that survived A/mountain lion infection, a clade 2.3.4.4b virus from 2024, suggesting that more recent clade 2.3.4.4b HA antigens such as A/Astrakhan may provide increased protection against A/bovine.”
Quote in the paperNot a substantial claim - Interpretationown data
Altered expression of HA by our repHA vaccines does not drive unique immunity.
“Our evaluation of sera from mice surviving H5N1 infection suggests our results extend to immunity elicited by authentic viral infection arguing against altered expression of HA by our repHA vaccines driving unique immunity.”
Quote in the paperNot a substantial claim - Interpretationreasoning
Currently circulating strains of H5N1 in the United States are sufficiently antigenically distinct to evade immunity elicited by historical HA antigens.
“Cumulatively, our findings here suggest that currently circulating strains of H5N1 in the United States are sufficiently antigenically distinct to evade immunity elicited by historical HA antigens.”
Quote in the paperSubstantial claim- Rests on an assumption: The A/bovine/OH/B24OSU-342/2024 isolate used in this study is representative of currently circulating H5N1 strains in the United States.
- Classified as probably not a substantial claim. 18
- May combine two claims. 19
- The quote only partly states this claim. 1
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationHumans with pre-existing influenza immunity vaccinated with an H5 vaccine developed greater broadly neutralizing antibody responses.
“Humans with pre-existing influenza immunity vaccinated with an H5 vaccine developed greater broadly neutralizing antibody responses11, suggesting pre-existing immunity may improve the breadth of response to H5N1 vaccination.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [11] Ellebedy, A. H. et al. Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans. Proc. Natl. Acad. Sci. USA 111, 13133–13138 (2014). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationA recent report evaluating an mRNA-based vaccine expressing the A/Astrakhan HA reported 3-fold lower neutralizing titers against A/pheasant/New York/22-009066-001/2022 that more closely matches the currently circulating H5N1 circulating in the United States.
“A recent report evaluating an mRNA-based vaccine expressing the A/Astrakhan HA reported 3-fold lower neutralizing titers against A/pheasant/New York/22-009066-001/2022 that more closely matches the currently circulating H5N1 circulating in the United States27.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [27] Furey, C. et al. Development of a nucleoside-modified mRNA vaccine against clade 2.3.4.4b H5 highly pathogenic avian influenza virus. Nat. Commun. 15, 4350 (2024). source
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe United States has approved H5N1 vaccines based on additional H5 HAs such as the Q-Pan H5N1 vaccine by GlaxoSmithKline which contains both A/Vietnam and the A/Indonesia/5/2005 H5N1 clade 2.1.3.2 HA.
“In addition, the United States has approved H5N1 vaccines based on additional H5 HAs such as the Q-Pan H5N1 vaccine by GlaxoSmithKline which contains both A/Vietnam and the A/Indonesia/5/2005 H5N1 clade 2.1.3.2 HA8,34”
Quote in the paperNot a substantial claim1 of 2 sources checked- cites [8] GSK. H5N1 vaccine approved by the U.S. FDA as pandemic influenza preparedness measure. https://www.gsk.com/en-gb/media/press-releases/h5n1-vaccine-approved-by-the-us-fda-as-pandemic-influenza-preparedness-measure/ (2013).
Couldn’t be matched to a paper in Crossref, so it can’t be checked.
- cites [34] Kim, J. H. et al. Immunogenicity and safety of AS03-adjuvanted H5N1 influenza vaccine in children 6-35 months of age: results from a phase 2, randomized, observer-blind, multicenter, dose-ranging study. Pediatr. Infect. Dis. J. 40, e333–e339 (2021). source
Materials and Methods (Vaccines, Schedule and Blinding; page unavailable) identifies the GSK Q-Pan vaccine used in the study as containing A/Indonesia/5/2005 clade 2.1.3.2 HA. The introductory passage says GSK vaccines contain A/Indonesia or A/Vietnam HA, not that this Q-Pan formulation contains both. The cited copy does not establish U.S. approval. (LLM, conf=0.88)
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationA lipid nanoparticle (LNP) delivered replicating RNA expressing the HA of clade 2.3.4A/Anhui/1/2005 H5N1 reported low homologous neutralizing activity after a single immunization that was increased after boosting.
“A recent report evaluating the immunogenicity in mice of a lipid nanoparticle (LNP) delivered replicating RNA expressing the HA of clade 2.3.4A/Anhui/1/2005 H5N1 reported low homologous neutralizing activity after a single immunization that was increased after boosting32.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [32] Cui, X. et al. Immunogenicity and biodistribution of lipid nanoparticle formulated self-amplifying mRNA vaccines against H5 avian influenza. NPJ Vaccines 9, 138 (2024). source
Classified as probably not a substantial claim. May combine two claims.
PremisecitationHumans receiving two doses of an investigational H5 vaccine based on clade 2.1.3 A/Indonesia/05/2005 PR8-IBCDC-RG2 failed to elicit neutralizing antibodies against A/Vietnam or vice versa, and heterologous prime-boost was necessary to elicit cross-neutralizing antibody responses.
“Humans receiving two doses of an investigational H5 vaccine based on clade 2.1.3A/Indonesia/05/2005 PR8-IBCDC-RG2 failed to elicit neutralizing antibodies against A/Vietnam or vice versa and instead heterologous prime-boost was necessary to elicit cross-neutralizing antibody responses21.”
Quote in the paperSubstantial claim1 of 1 sources checked- cites [21] Belshe, R. B. et al. Safety and immunogenicity of influenza A H5 subunit vaccines: effect of vaccine schedule and antigenic variant. J. Infect. Dis. 203, 666–673 (2011). source
Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.
Experimental — accuracy not yet measured
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationVaccination of chickens with recombinant viruses with clade 2.3.4.4 or 2.2.1.2 HAs showed strong homologous protection but incomplete heterologous protection.
“Vaccination of chickens with recombinant viruses with clade 2.3.4.4 or 2.2.1.2 HAs showed strong homologous protection but incomplete heterologous protection28 further suggesting that broad homosubtypic immunity may not always be achieved.”
Quote in the paperNot a substantial claim1 of 1 sources checked- cites [28] Mahmoud, S. H. et al. Immunogenicity and cross-protective efficacy induced by an inactivated recombinant avian influenza A/H5N1 (Clade 2.3.4.4b) vaccine against co-circulating influenza A/H5Nx viruses. Vaccines 11, 1397 (2023). source
May combine two claims. The quote only partly states this claim.
Findingown dataBoth repHA-Vietnam and repHA-Bovine elicited significant binding antibodies to HAs from A/duck/Laos/3295/2006 and A/bald eagle/Florida/W22-134-OP/2022.
“Both repHA-Vietnam and repHA-Bovine elicited significant binding antibodies to HAs from A/duck/Laos/3295/2006 or A/bald eagle/Florida/W22-134-OP/2022 (Supplemental Fig. 2).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataMice vaccinated with repNP + repHA did not have detectable neutralizing activity despite having similar binding titers as mice vaccinated with repHA-Bovine alone.
“Mice vaccinated with repNP + repHA despite having similar binding titers as mice vaccinated with repHA-Bovine alone, did not have detectable neutralizing activity (Fig. 2c) perhaps reflecting the lower dose of repHA-Bovine these mice received in the combination vaccination.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataFour of six repHA-Vietnam vaccinated mice succumbed to A/bovine infection with a mean time to death of 8.5 days, while two mice exhibited no clinical disease.
“Surprisingly, four of six repHA-Vietnam mice also succumbed to the infection with a MTD of 8.5 days (Fig. 2e, f) while two mice exhibited no clinical disease following challenge (Fig. 2e, f), suggesting repHA-Vietnam provided incomplete protection against heterologous A/bovine challenge.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataBoth repHA-Vietnam and repHA-Bovine elicited HA-specific T cells.
“Both repHA-Vietnam and repHA-Bovine elicited HA-specific T cells while repNP failed to elicit HA-specific T cells as expected (Fig. 2d).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataRepHA-Bovine elicited antibodies that had strong binding to A/bovine, significantly greater than repHA-Vietnam vaccination, but with significantly reduced binding activity against many H5 clades compared to repHA-Vietnam vaccination.
“In contrast, repHA-Bovine elicited antibodies that had strong binding to A/bovine, significantly greater than repHA-Vietnam vaccination, but with significantly reduced binding activity against many H5 clades compared to repHA-Vietnam vaccination (Fig. 3a, b).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataSignificant reactivity to NP was measured in repNP-vaccinated mice.
“Significant reactivity to NP was also measured in repNP-vaccinated mice (Fig. 2b).”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataRepHA-Vietnam and repHA-Bovine elicit HA-binding antibodies after a single immunization.
“These data suggest that while repHA-Vietnam and repHA-Bovine elicit HA-binding antibodies after a single immunization, neutralizing activity is low or absent, may be dose-dependent and the mutations between A/Vietnam and A/bovine can impact nAb binding and neutralization activity.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataRepHA-Bovine vaccinated mice had virus neutralization titers of 1:30 against homologous A/bovine but no detectable neutralization against heterologous A/Vietnam.
“RepHA-Bovine vaccinated mice had VN titers of 1:30 against homologous A/bovine but no detectable neutralization against heterologous A/Vietnam (Fig. 2c).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataRepHA-Vietnam vaccinated mice had low but detectable virus neutralization titers of 1:20 against homologous A/Vietnam but no detectable neutralization against heterologous A/bovine.
“RepHA-Vietnam vaccinated mice had low but detectable virus neutralization (VN) titers of 1:20 against homologous A/Vietnam but no detectable neutralization against heterologous A/bovine (Fig. 2c).”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataThese human sera also had antibodies that bound H9, H6 and H10 HAs.
“These sera also had antibodies that bound H9, H6 and H10 HAs (Supplemental Fig. 4).”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Findingown dataHuman sera from H5N1 vaccinated individuals or a convalescent H1N1 infected individual had reactivity to most H3 and H1 HAs tested.
“Human sera from H5N1 vaccinated individuals or a convalescent H1N1 infected individual had reactivity to most H3 and H1 HAs tested, likely through vaccination or exposure to seasonal influenza (Supplemental Fig. 4).”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataThe repRNA vaccines were immunogenic, with repHA-Vietnam and repHA-Bovine eliciting both humoral and cellular immunity.
“Cumulatively, these data indicate that our repRNA vaccines were immunogenic with repHA-Vietnam and repHA-Bovine eliciting both humoral and cellular immunity.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataThe A/Vietnam and A/bovine HA antigens elicit antibodies either through vaccination or infection with distinct homosubtypic binding profiles, possibly due to targeting of different epitopes within the HA.
“Cumulatively, these data suggest that the A/Vietnam and A/bovine HA antigens elicit antibodies either through vaccination or infection with distinct homosubtypic binding profiles possibly due to targeting of different epitopes within the HA.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationWT C57BL/6J mice are highly susceptible to A/bovine challenge, rapidly developing lethal respiratory and neurological disease.
“We have recently shown that WT C57BL/6J mice are highly susceptible to A/bovine challenge with mice rapidly developing lethal respiratory and neurological disease17.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Tipih, T. et al. Recent bovine HPAI H5N1 isolate is highly virulent for mice, rapidly causing acute pulmonary and neurologic disease. Preprint at bioRxiv https://doi.org/10.1101/2024.08.19.608652 (2024). source
May combine two claims.
InterpretationreasoningPre-existing immunity, species-specific determinants, and/or the clade 2.1.3 HA utilized may improve the breadth of homosubtypic H5 HA reactivity.
“However, the human sera also reacted strongly to the A/bovine HA similar to our repHA-Bovine vaccinated mice (Fig. 3a) suggesting that pre-existing immunity, species-specific determinants, and/or the clade 2.1.3 HA utilized may improve the breadth of homosubtypic H5 HA reactivity.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe challenge virus was titrated in parallel to confirm challenge with 4 HAUs.
“The challenge virus was titrated in parallel to confirm challenge with 4 HAUs.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenThe virus was sequenced to confirm identity and exclude biological contamination.
“and sequenced to confirm identity and exclude biological contamination.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing), S4 (based).
Interpretationnone givenThe partial protection conferred by a historical HA is likely due to mutations in the HA head domain.
“In contrast, a historical HA, as utilized by some stockpiled vaccines, conferred only partial protection, likely due to mutations in the HA head domain.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Study design and conductnone givenAssays were performed on pooled serum (n = 4 mice per group) and measured in duplicate.
“Assays were performed on pooled serum (n = 4 mice per group) and measured in duplicate.”
Quote in the paperNot a substantial claimMay combine two claims.
InterpretationcitationBoosting or higher vaccine doses may increase the neutralization capacity of repRNA-elicited antibodies.
“These data suggest boosting or higher vaccine doses may increase the neutralization capacity of repRNA-elicited antibodies.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationHigher tolerable single vaccine doses would be possible with the repRNA/LIONTM platform.
“The repRNA/LION™ platform is less reactogenic than traditional LNPs suggesting higher tolerable single vaccine doses would be possible33.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenWe did not evaluate actual stockpiled vaccines that utilize distinct vaccine platforms.
“although we utilized a repRNA expressing the A/Vietnam HA as utilized by some stockpiled vaccines, we did not evaluate actual stockpiled vaccines that utilize distinct vaccine platforms.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationA stockpiled H5N1 vaccine utilizing the clade 1 A/Vietnam HA can elicit cross-neutralizing antibodies to clade 2.3.4.4b H5N1 in vaccinated humans, though the report did not evaluate contemporary 2024 H5N1 isolates.
“It has recently been reported that a stockpiled H5N1 vaccine utilizing the clade 1A/Vietnam HA can elicit cross-neutralizing antibodies to clade 2.3.4.4b H5N1 in vaccinated humans29, though the report did not evaluate contemporary 2024 H5N1 isolates.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Khurana, S. et al. Licensed H5N1 vaccines generate cross-neutralizing antibodies against highly pathogenic H5N1 clade 2.3.4.4b influenza virus. Nat. Med. 30, 2771–2776 (2024). source
Classified as probably not a substantial claim. May combine two claims.
Study design and conductown dataRNA was characterized by capillary gel electrophoresis to confirm production of full-length product and activity, including the production of the encoded protein, confirmed by western blot and immunofluorescence of cells transfected with each RNA.
“RNA was characterized by capillary gel electrophoresis to confirm production of full-length product and activity, including the production of the encoded protein, confirmed by western blot and immunofluorescence of cells transfected with each RNA.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone givenMale and female C57BL6/J mice 8 weeks of age were randomly assigned to study groups.
“Male and female C57BL6/J mice 8 weeks of age were purchased directly from Jackson and randomly assigned to study groups.”
Quote in the paperNot a substantial claim
The paper relies on this without support.
Neutralizing antibodies are often the major correlate of vaccine-mediated protection against influenza.
“As the HA head is an immunodominant target of vaccine-induced immunity11 and nAbs are often the major correlate of vaccine-mediated protection against influenza, the sequence variation in the A/bovine HA could impact the protective capacity of vaccines using previously circulating H5N1 HAs.”
The paper relies on this without support.
The A/bovine/OH/B24OSU-342/2024 isolate used in this study is representative of currently circulating H5N1 strains in the United States.
“Cumulatively, our findings here suggest that currently circulating strains of H5N1 in the United States are sufficiently antigenically distinct to evade immunity elicited by historical HA antigens.”
Cites
Potent protection against H5N1 and H7N9 influenza via childhood hemagglutinin imprinting
Gostic, K. M., Ambrose, M. R., Worobey, M., & Lloyd‐Smith, J. O. (2016) · Science · doi:10.1126/science.aag1322 · Cited by 464 · see citing works
Nguyen, T.-Q., Hutter, C. R., Markin, A., Thomas, M. N., Lantz, K., Killian, M. L., Janzen, G. M., Vijendran, S., Wagle, S., Inderski, B., et al. (2025) · Science · doi:10.1126/science.adq0900 · Cited by 253 · see citing works
A Site of Vulnerability on the Influenza Virus Hemagglutinin Head Domain Trimer Interface
Bangaru, S., Lang, S., Schotsaert, M., Vanderven, H. A., Zhu, X., Kose, N., Bombardi, R. G., Finn, J. A., Kent, S. J., Gilchuk, P., et al. (2019) · Cell · doi:10.1016/j.cell.2019.04.011 · Cited by 246 · see citing works
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., et al. (2020) · Science Translational Medicine · doi:10.1126/scitranslmed.abc9396 · Cited by 241 · see citing works
Self-citationEllebedy, A. H., Krammer, F., Li, G.-M., Miller, M. S., Chiu, C., Wrammert, J., Chang, C. Y., Davis, C. W., McCausland, M., Elbein, R., et al. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1414070111 · Cited by 234 · see citing works
Original Antigenic Sin: How First Exposure Shapes Lifelong Anti–Influenza Virus Immune Responses
Zhang, A., Stacey, H. D., Mullarkey, C. E., & Miller, M. S. (2019) · The Journal of Immunology · doi:10.4049/jimmunol.1801149 · Cited by 195 · see citing works
Erasmus, 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-citationA recurring motif for antibody recognition of the receptor-binding site of influenza hemagglutinin
Xu, R., Krause, J. C., McBride, R., Paulson, J. C., Crowe, J. E., & Wilson, I. A. (2013) · Nature Structural & Molecular Biology · doi:10.1038/nsmb.2500 · Cited by 133 · see citing works
Garg, S., Reed, C., Davis, C. T., Uyeki, T. M., Behravesh, C. B., Kniss, K. L., Budd, A., Biggerstaff, M., Adjemian, J., Barnes, J., et al. (2024) · MMWR Morbidity and Mortality Weekly Report · doi:10.15585/mmwr.mm7321e1 · Cited by 118 · see citing works
Emergence and interstate spread of highly pathogenic avian influenza A(H5N1) in dairy cattlePreprint
Nguyen, T.-Q., Hutter, C. R., Markin, A., Thomas, M. R., Lantz, K., Killian, M. L., Janzen, G. M., Vijendran, S., Wagle, S., Inderski, B., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.01.591751 · Cited by 104 · see citing works
Khan, S. U., Anderson, B. D., Heil, G. L., Liang, S., & Gray, G. C. (2015) · Journal of Infectious Diseases · doi:10.1093/infdis/jiv109 · Cited by 88 · see citing works
Furey, C., Scher, G., Ye, N., Kercher, L., DeBeauchamp, J., Crumpton, J. C., Jeevan, T., Patton, C., Franks, J., Rubrum, A., et al. (2024) · Nature Communications · doi:10.1038/s41467-024-48555-z · Cited by 79 · see citing works
An Omicron-specific, self-amplifying mRNA booster vaccine for COVID-19: a phase 2/3 randomized trial
Saraf, A., Gurjar, R., Kaviraj, S., Kulkarni, A., Kumar, D., Kulkarni, R., Virkar, R., Krishnan, J., Yadav, A., Baranwal, E., et al. (2024) · Nature Medicine · doi:10.1038/s41591-024-02955-2 · Cited by 66 · see citing works
Zhu, X., Guo, Y., Jiang, T., Wang, Y., Chan, K., Li, X., Yu, W., McBride, R., Paulson, J. C., Yuen, K., et al. (2013) · Journal of Virology · doi:10.1128/jvi.01577-13 · Cited by 65 · see citing works
Belshe, R. B., Frey, S. E., Graham, I., Mulligan, M. J., Edupuganti, S., Jackson, L. A., Wald, A., Poland, G., Jacobson, R., Keyserling, H. L., et al. (2011) · The Journal of Infectious Diseases · doi:10.1093/infdis/jiq093 · Cited by 62 · see citing works
Khurana, S., King, L. R., Manischewitz, J., Posadas, O., Mishra, A. K., Liu, D., Beigel, J. H., Rappuoli, R., Tsang, J. S., & Golding, H. (2024) · Nature Medicine · doi:10.1038/s41591-024-03189-y · Cited by 57 · 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
Self-citationInactivation of Avian Influenza A(H5N1) Virus in Raw Milk at 63°C and 72°C
Kaiser, F. K., Morris, D. H., Wickenhagen, A., et al. (2024) · New England Journal of Medicine · doi:10.1056/nejmc2405488 · Cited by 42 · see citing works
Cui, 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
HUANG, S. Y., YANG, J. R., LIN, Y. J., YANG, C. H., CHENG, M. C., LIU, M. T., WU, H. S., & CHANG, F. Y. (2015) · Epidemiology and Infection · doi:10.1017/s0950268815000394 · Cited by 31 · 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
Self-citationHawman, D. W., Leventhal, S. S., Meade-White, K. D., Khandhar, A. P., Murray, J., Lovaglio, J., Shaia, C., Saturday, G. A., Hinkley, T. C., Erasmus, J. H., et al. (2024) · npj Vaccines · doi:10.1038/s41541-024-00887-z · Cited by 21 · see citing works
Self-citationQi, W., Su, S., Xiao, C., Zhou, P., Li, H., Ke, C., Gray, G. C., Zhang, G., & Liao, M. (2014) · BMC Medicine · doi:10.1186/s12916-014-0205-3 · Cited by 15 · see citing works
Kim, J. H., Drame, M., Puthanakit, T., Chiu, N.-C., Supparatpinyo, K., Huang, L.-M., Chiu, C.-H., Chen, P.-Y., Hwang, K.-P., Danier, J., et al. (2021) · Pediatric Infectious Disease Journal · doi:10.1097/inf.0000000000003247 · Cited by 14 · see citing works
Mahmoud, S. H., Khalil, A. A., Abo Shama, N. M., El Sayed, M. F., Soliman, R. A., Hagag, N. M., Yehia, N., Naguib, M. M., Arafa, A.-S., Ali, M. A., et al. (2023) · Vaccines · doi:10.3390/vaccines11091397 · Cited by 14 · see citing works
Accelerated prime-and-trap vaccine regimen in mice using repRNA-based CSP malaria vaccine
MacMillen, Z., Hatzakis, K., Simpson, A., Shears, M. J., Watson, F., Erasmus, J. H., Khandhar, A. P., Wilder, B. K., Murphy, S. C., Reed, S. G., et al. (2024) · npj Vaccines · doi:10.1038/s41541-023-00799-4 · Cited by 13 · see citing works
Self-citationTipih, T., Mariappan, V., Yinda, K. C., Meade-White, K., Lewis, M., Okumura, A., McCarthy, N., Clancy, C., de Wit, E., Munster, V. J., et al. (2024) · doi:10.1101/2024.08.19.608652 · Cited by 10 · see citing works
Self-citationHawman, D., Leventhal, S., Meade-White, K., et al. (2024) · doi:10.21203/rs.3.rs-3835275/v1 · Cited by 1
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- GSK. H5N1 vaccine approved by the U.S. FDA as pandemic influenza preparedness measure. https://www.gsk.com/en-gb/media/press-releases/h5n1-vaccine-approved-by-the-us-fda-as-pandemic-influenza-preparedness-measure/ (2013).
Cited by
Sorted by citations
Lasrado, N., Wang, L., Liu, J., Rössler, A., Chaudhari, J., Wang, Q., Stone, J. J., Granados-Contreras, F. A., Wu, J., Cabrera-Barragan, D. N., et al. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.ady2282 · Cited by 11 · see citing works
Highly Pathogenic Avian Influenza (H5N1) Clade 2.3.4.4b in Cattle: A Rising One Health Concern
Sanchez-Rojas, I. C., Bonilla‐Aldana, D. K., Solarte-Jimenez, C. L., Bonilla-Aldana, J. L., Acosta-España, J. D., & Rodriguez-Morales, A. J. (2025) · Animals · doi:10.3390/ani15131963 · Cited by 14 · see citing works
Yakovlev, V. A., Litvinova, V. R., Борисовна, Р. Н., Borgoyakova, M. B., Tigeeva, E. V., Starostina, E. V., Ivanova, K. I., Gudymo, A. S., Danilchenko, N. V., Perfilyeva, O. N., et al. (2025) · Vaccines · doi:10.3390/vaccines13080883 · Cited by 7 · see citing works
Immunogenicity and safety of a rabies-based highly pathogenic influenza A virus H5 vaccine in cattle
Paran, N., Wirblich, C., Olal, C., et al. (2025) · npj Vaccines · doi:10.1038/s41541-025-01238-2 · Cited by 6 · see citing works
“While mouse study by Hawman and collaborators 13 using a replicating RNA vaccine indicated that a clade 2.3.4.4b, but not clade 1 HA-based vaccine, protects against H5N1 (cattle) challenge in mice, our cattle study and importantly human studies demonstrated the ability of clade 1 H5N1 vaccine to…”
InfluentialDosey, A. M., Dadonaite, B., Gillespie, R. A., Leaf, E. M., Vukovich, M. J., McGowan, J., Grey, E., Muramatsu, H., Jun, R. H. J., Pardi, N., et al. (2026) · Science Translational Medicine · doi:10.1126/scitranslmed.aea8770 · Cited by 6 · see citing works
Influenza mRNA vaccine reduces pathogenicity and transmission of A(H5N1) virus in a ferret model
Hatta, M., Brock, N., Hauguel, T., Feng, C., Huang, Y., Ritter, J. M., Hatta, Y., Keller, M. W., de Souza, I. P., Hossain, J., et al. (2025) · npj Vaccines · doi:10.1038/s41541-025-01318-3 · Cited by 8 · see citing works
“Speci fi cally, Hatta 27,54 – 56 .”
Fast and flu-rious: How to prevent and treat emerging influenza A viruses
Sesifredo, I., Batalha, I. L., & Amorim, M. J. (2025) · PLoS Pathogens · doi:10.1371/journal.ppat.1013135 · Cited by 4 · see citing works
Preclinical evaluation of an mRNA vaccine developed from the first human isolate of bovine H5N1
Li, H., Huang, M., Feng, S., Li, W., Wei, D., Li, X., Quan, Y., Gu, H. S., Jiang, T., Liu, Y., et al. (2026) · Cell Reports Medicine · doi:10.1016/j.xcrm.2026.102702 · Cited by 4 · see citing works
“35 Furthermore, while Ast20-based vaccine showed partial cross-reactivity, their neutralizing titers were lower against phylogenetically Texas-closer isolates (e.g., A/pheasant/New York/22-009066-001/2022).”
Donbraye, E., McLeod, L., Carson, C. N., Chai, Z., Lacoste, S. R., Herman, E. K., McCarthy, E. L., Hill, J. E., Erickson, N. E. N., Pollock, C. M., et al. (2026) · Frontiers in Veterinary Science · doi:10.3389/fvets.2025.1704412 · Cited by 3 · see citing works
Potent efficacy of an NA-targeting antibody against a broad spectrum of H5N1 influenza viruses
Moriyama, S., di Iulio, J., Zatta, F., Hauser, K., Asanuma, H., Munoz, H. E., Errico, J. M., Adachi, Y., Dang, H. V., Czudnochowski, N., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-70036-8 · Cited by 1 · see citing works
“…stockpiled for a pandemic response, long-term pre-exposure prophylaxis may be challenging for the small molecules due to their shorthalf-life 44 ,andH5vaccinescouldfacedrawbacksincommonwith seasonal in fl uenza vaccines, such as mismatch, poor immunogenicity, and immunological imprinting 24,45,46 .”
Hawman, D. W., Griffin, A., McCarthy, N., Okumura, A., Leventhal, S. S., Agumamidi, M., Chorabik, M., Altynova, E. S., Lewis, M. C., Hinkley, T. C., et al. (2025) · Science Translational Medicine · doi:10.1126/scitranslmed.adw4646 · Cited by 2 · see citing works
Self-citationAebischer, A., Günther, A., Piesche, R., et al. (2026) · Journal of Clinical Microbiology · doi:10.1128/jcm.01907-25 · Cited by 1 · see citing works
Ying, B., Pyles, K. D., Darling, T. L., Seehra, K., Pham, T., Huang, L.-C., Harastani, H., Sharma, A., Desai, P., Kashentseva, E. A., et al. (2026) · Cell Reports Medicine · doi:10.1016/j.xcrm.2025.102582 · Cited by 1 · see citing works
“…studies using various intramuscularly (IM) administered mRNA lipid nanoparticles (mRNA-LNP) and replicating RNA vaccines targeting clade 2.3.4.4b 26–28 How these results translate to humans remains to be determined, including whether they will prevent upper airway infection and transmission.”
InfluentialLam, J.-Y., Yuen, C., Cheung, S.-K., Cheung, P.-H., Yuen, K.-Y., & Kok, K. (2026) · EBioMedicine · doi:10.1016/j.ebiom.2026.106228 · Cited by 1 · see citing works
Dosey, A. M., Dadonaite, B., Gillespie, R. A., Leaf, E. M., Vukovich, M. J., McGowan, J., Grey, E., Muramatsu, H., Jun, R. H. J., Pardi, N., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.07.30.667762 · Cited by 1 · see citing works
“Greatly improved production speed has been achieved through the advent of mRNA vaccines, which enable a single manufacturing process for any sequence (13, 14) .”
An Overview of the H5N1 mRNA Vaccine Pipeline
Focosi, D., Nicastri, E., & Maggi, F. (2025) · Influenza and Other Respiratory Viruses · doi:10.1111/irv.70113
“At least 20 H 5 N 1 - based vaccines have been already authorized for human use across the globe [1], but in animal models, they only provide partial immunity against the currently dominant 2.3.4.4b clade [2].”
InfluentialT Cell Responses to Influenza Infections in Cattle
Hada, A., & Xiao, Z. (2025) · Viruses · doi:10.3390/v17081116 · Cited by 1 · see citing works
“…is no commercially available vaccine specifically approved for influenza in cattle, a recent study has demonstrated that a replicating RNA (repRNA) vaccine expressing the HA of H5N1 virus isolated from a U.S. dairy cow conferred complete protection against homologous lethal challenge in mice [243].”
Immunogenicity and efficacy of a rabies-based vaccine against highly pathogenic influenza H5N1 virus
Paran, N., Wirblich, C., Albrecht, R. A., et al. (2026) · Emerging Microbes & Infections · doi:10.1080/22221751.2026.2620221
“While studies highlight the critical role of matching the antigen in the vaccine and in the target pathogen [36], other studies, including the current study, demonstrate the ability of unmatched vaccines (different clade) to induce protective immunity [15,35,37].”
Zhang, K., Wang, Y., Wang, X., Wang, F., Xu, G., Wang, J., Wang, Z., Cheng, Y., Wang, H., Yan, Y., et al. (2026) · Veterinary Sciences · doi:10.3390/vetsci13090869
“In contrast, the repRNA study in mice showed that immunity elicited by the historical A/Viet Nam/1203/2004 HA provided substantially weaker protection against contemporary bovine H5N1 than a matched clade 2.3.4.4b HA [60].”
InfluentialFlitter, B. A., Tam, K., Showalter, L. J., Sun, W., & Tucker, S. N. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1863888
- Authors
- Hawman, D. W., Tipih, T., Hodge, E., Stone, E. T., Warner, N., McCarthy, N., Granger, B., Meade-White, K., Leventhal, S., Hatzakis, K., Park, S., Gaffney, K., Rosenke, K., Erasmus, J. H., & Feldmann, H.
- Affiliations
- National Institutes of Health (US)
- Corresponding author
- Hawman, David W.
- Erasmus, Jesse H.
- Feldmann, Heinz
- ORCID
- Venue
- Nature Communications
- Published
- 2025-01-14
- Volume
- 16
- Issue
- 1
- Pages
- 655-655
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11732985
- OpenAlex
- W4406360884
- Semantic Scholar
- 821d2fab28b8dbce51c6f8632266e3661b873042
- Cited by
- 20
- References
- 27
- Citations by year
- 2026: 10 · 2025: 10
- FWCI
- 12.43
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Research Square (acceptedVersion, cc-by)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Health Sciences › Medicine › Epidemiology › Influenza Virus Research Studies
- Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Keywords
- H5N1 avian influenza, bovine influenza, hemagglutinin, nucleic acid vaccines, clade 2.3.4.4b, vaccine stockpile, antigenic drift, immune evasion, pandemic preparedness, mouse challenge protection
- MeSH terms
- mRNA Vaccines, Animals, Antibodies, Viral, Cattle, Cattle Diseases, Female, Humans, Influenza Vaccines, Mice, Inbred BALB C, Orthomyxoviridae Infections, Hemagglutinin Glycoproteins, Influenza Virus, Mice, Influenza A Virus, H5N1 Subtype
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-11.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-11.
Cited sources are checked by gpt-6-sol.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
