mRNA mediates passive vaccination against infectious agents, toxins, and tumors

It is possible to generate protective mAbs against many viruses and microorganisms.

“there is ample evidence that it is possible to generate protective mAbs against many viruses and microorganisms (Teitelbaum et al, 1998; Nosanchuk et al, 2003; Both et al, 2013).”

• cites Teitelbaum et al, 1998 sourceNot checked — no full text of the source
• cites Nosanchuk et al, 2003 sourceSupported
• cites Both et al, 2013 sourcePartly supported

  The Development of monoclonal antibodies section reports that many antiviral mAbs have been developed, and the Antiviral immunity section describes protection in mAb-treated mice. The paper supports the claim for viruses, but the passages do not establish it for other microorganisms (searched: bacteria, fungi, parasites, and nonviral pathogens). No page numbers are available in our copy. (LLM, conf=0.87)

  Experimental — accuracy not yet measured

Protection afforded by currently licensed vaccines is primarily based on induction of a humoral immune response.

“Protection afforded by currently licensed vaccines is primarily based on induction of a humoral immune response (Amanna & Slifka, 2011).”

• cites Amanna & Slifka, 2011 sourcePartly supported

  The section “Persisting antibody following vaccination; the first line of defense against infection” says antibody responses are the probable basis of efficacy for many of today’s most successful vaccines. But the Abstract and Conclusions say the relative contribution of humoral immunity depends on the vaccine and pathogen, and that protection often also involves cellular immunity. The claim extends the antibody-based account to currently licensed vaccines generally. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

In 2003, a cocktail of mAbs was developed which protected Syrian hamsters from lethal challenges with a highly virulent rabies virus strain in post-exposure scenarios.

“In 2003, a cocktail of mAbs was developed which protected Syrian hamsters from lethal challenges with a highly virulent rabies virus strain in post‐exposure scenarios (Prosniak et al, 2003).”

• cites Prosniak et al, 2003 sourceSupported

Physiological responses elicited in primates and domestic pigs treated with an mRNA-encoded hormone have suggested the feasibility of mRNA for large animal therapies.

“Physiological responses elicited in primates and domestic pigs treated with an mRNA‐encoded hormone have suggested the feasibility of mRNA for large animal therapies (Thess et al, 2015).”

• cites Thess et al, 2015 sourceSupported

Conclusive data have also been presented for mRNA as a platform for protein (replacement) therapies.

“Conclusive data have also been presented for mRNA as a platform for protein (replacement) therapies (Kormann et al, 2011; Kariko et al, 2012; Zangi et al, 2013; Thess et al, 2015; Balmayor et al, 2016).”

• cites Kormann et al, 2011 sourceNot checked — no full text of the source
• cites Kariko et al, 2012 sourceSupported
• cites Zangi et al, 2013 sourcePartly supported

  The Abstract and Results report that VEGF-A modRNA produced a therapeutic protein and improved cardiac outcomes in a mouse model of myocardial infarction. This supports mRNA as a potential platform for protein-based therapy, but the paper does not demonstrate protein replacement therapy specifically or establish conclusive efficacy across such therapies. Page numbers were not supplied in our copy. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

In B cells, solitary heavy chains are retained at the endoplasmic reticulum by the chaperone binding immunoglobulin protein (BiP).

“In B cells, solitary heavy chains are retained at the endoplasmic reticulum by the chaperone binding immunoglobulin protein (BiP) (Hendershot et al, 1987).”

• cites Hendershot et al, 1987 sourceSupported

The monoclonal antibody S057 (CR57) provides broad neutralization of a variety of rabies virus strains via binding to glycoprotein G.

“we selected the monoclonal antibody S057, also well known as CR57, one component of the published mAb cocktail, because it provides broad neutralization of a variety of rabies virus strains via binding to glycoprotein G.”

• cites Prosniak et al, 2003 sourcePartly supported

  The passage labeled Abstract and Table 1 identify SO57 as a cocktail component and report neutralization of several fixed and street rabies-virus strains. Our copy does not identify SO57 as CR57 or say that its neutralization occurs through binding to rabies-virus glycoprotein G; its glycoprotein discussion concerns the expression vector instead. Page numbers were not supplied. (LLM, conf=0.86)

  Experimental — accuracy not yet measured

For both VNAs, serum half-lives were calculated to be in the range of 24-36 h.

“For both VNAs, serum half‐lives were calculated to be in the range of 24–36 h which is in line with a previous report (Mukherjee et al, 2014).”

• cites Mukherjee et al, 2014 sourceSupported

Short-lived proteins can significantly profit by being expressed from mRNA (Kariko et al, 2012; Thess et al, 2015).

“By contrast, short‐lived proteins can significantly profit by being expressed from mRNA (Kariko et al, 2012; Thess et al, 2015).”

• cites Kariko et al, 2012 sourceSupported
• cites Thess et al, 2015 sourceSupported

It is likely that target-specific mRNA optimizations and further improvements to the formulation can substantially increase efficacy (Thess et al, 2015).

“Thirdly, in light of previous findings, it is likely that target‐specific mRNA optimizations and further improvements to the formulation can substantially increase efficacy (Thess et al, 2015).”

• cites Thess et al, 2015 sourceSupported

An earlier study on erythropoietin revealed that findings in a murine model translated to larger animals such as domestic pigs as well as to primates (Thess et al, 2015).

“An earlier study on a different secreted protein, erythropoietin, revealed that findings in a murine model translated to larger animals such as domestic pigs as well as to primates (Thess et al, 2015).”

• cites Thess et al, 2015 sourceSupported

VNAs with an estimated serum half-life of 1-2 days (with albumin-binding) should benefit from being encoded by mRNA (Mukherjee et al, 2014).

“Accordingly, VNAs with an estimated serum half‐life of 1–2 days (with albumin‐binding) should benefit from being encoded by mRNA (Mukherjee et al, 2014).”

• cites Mukherjee et al, 2014 sourcePartly supported

  The Discussion (page not provided) estimates a 1–2-day serum half-life for the albumin-binding VNA in mice and says continuous genetic expression can improve VNA serum levels. The Introduction mentions RNA as a possible delivery vehicle, but the study tested adenoviral DNA delivery, not mRNA-encoded VNAs; it does not establish the claimed benefit of mRNA encoding. (LLM, conf=0.85)

  Experimental — accuracy not yet measured

Expression of therapeutic proteins can also be achieved by intramuscular administration (Schlake et al, 2012).

“Moreover, expression of therapeutic proteins can also be achieved by intramuscular administration (Schlake et al, 2012).”

• cites Schlake et al, 2012 sourceSupported

mRNA-LNP enabled prophylactic and therapeutic protection against lethal rabies infection.

“thereby enabling both prophylactic and therapeutic protection against lethal rabies infection or botulinum intoxication.”

Single injections of mRNA-lipid nanoparticle (LNP) were sufficient to establish rapid, strong, and long-lasting serum antibody titers in vivo.

“Single injections of mRNA–lipid nanoparticle (LNP) were sufficient to establish rapid, strong, and long‐lasting serum antibody titers in vivo”

mRNA-LNP enabled prophylactic and therapeutic protection against botulinum intoxication.

“thereby enabling both prophylactic and therapeutic protection against lethal rabies infection or botulinum intoxication.”

Therapeutic mRNA-mediated antibody expression allowed mice to survive an otherwise lethal tumor challenge.

“Moreover, therapeutic mRNA‐mediated antibody expression allowed mice to survive an otherwise lethal tumor challenge.”

The flexibility of the mRNA technology was further illustrated by complementary data from additional indications, including the demonstration of therapeutic efficacy in a tumor model.

“The flexibility of the mRNA technology was further illustrated by complementary data from additional indications, including the demonstration of therapeutic efficacy in a tumor model.”

Supernatants containing mRNA-encoded VNA-Stx2 proved capable to protect cell viability in the presence of Shiga toxin with potency comparable to recombinant VNA-Stx2.

“Finally, supernatants containing mRNA‐encoded VNA‐Stx2 proved capable to protect cell viability in the presence of Shiga toxin with potency comparable to recombinant VNA‐Stx2 (Fig 2B).”

Light chains were also secreted in the absence of heavy chains.

“In contrast, light chains were also secreted in the absence of heavy chains.”

The estimated serum half-life of anti-influenza mAb was also about 1 week.

“The estimated serum half‐life of this antibody was also about 1 week.”

Early kinetics appeared similar for mAbs and VNAs.

“Thus, early kinetics appeared similar for mAbs and VNAs.”

Specific activity of mRNA-derived anti-HIV mAb was comparable to the respective recombinant protein by measuring the inhibition of virus entry into reporter cells.

“Specific activity of mRNA‐derived anti‐HIV mAb was demonstrated to be comparable to the respective recombinant protein by measuring the inhibition of virus entry into reporter cells (Fig 2F and Appendix Fig S6).”

Serum titers dropped much faster for VNAs than for mAbs after day 2.

“However, serum titers dropped much faster for VNAs than for mAbs after day 2.”

Peak serum levels were reached 6-24 h after administration.

“Peak serum levels were reached 6–24 h after administration.”

Heavy-chain retention for mRNA-mediated expression was confirmed in overexpressing non-B cells, including a hepatic cell line that may mimic in vivo conditions in the liver.

“Heavy‐chain retention for mRNA‐mediated expression was confirmed in overexpressing non‐B cells, including a hepatic cell line that may mimic in vivo conditions in the liver, our target organ for in vivo delivery (Appendix Fig S1).”

Specific antigen binding of mAbs against rabies, influenza, and human CD20 was verified by staining of antigen-expressing target cells.

“Specific antigen binding of mAbs against rabies, influenza, and human CD20 was verified by staining of antigen‐expressing target cells (Fig 2C–E and Appendix Fig S5).”

Supernatants containing mRNA-encoded VNA-BoNTA had neutralizing potency comparable to a recombinant VNA-BoNTA protein standard.

“VNA‐BoNTA functionality was confirmed by a SNAP25 cleavage inhibition assay demonstrating that supernatants containing mRNA‐encoded VNA‐BoNTA had neutralizing potency comparable to a recombinant VNA‐BoNTA protein standard (Fig 2A).”

In both disease models, high levels of in vivo serum expression were obtained that conferred full protection in pre- and post-exposure scenarios.

“In both disease models, high levels of in vivo serum expression were obtained that conferred full protection in pre‐ and post‐exposure scenarios.”

In vitro antibody mRNA half-life in primary mouse hepatocytes was approximately 15 h.

“In vitro antibody mRNA half‐life in primary mouse hepatocytes was approximately 15 h (Appendix Fig S4A).”

Mice that received mRNA coding for anti-influenza mAb all revealed the same high serum levels after 24 days.

“In contrast, mice that received mRNA coding for anti‐influenza mAb all revealed the same high serum levels after 24 days (Fig 3D).”

A single injection of increasing mRNA-LNP doses induced rising serum levels of antibody without reaching peak levels up to the highest doses tested.

“A single injection of increasing mRNA‐LNP doses induced rising serum levels of antibody without reaching peak levels up to the highest doses tested in this study (Fig 3A and Appendix Fig S7A).”

Expression of VNAs against botulinum neurotoxin serotype A (VNA-BoNTA) and Shiga toxin 2 (VNA-Stx2) was readily detected by Western blot and antigen-specific ELISA.

“Likewise, expression of VNAs against botulinum neurotoxin serotype A (VNA‐BoNTA) and Shiga toxin 2 (Stx2) from E. coli (O157:H7) (VNA‐Stx2) was readily detected by Western blot and antigen‐specific ELISA (Fig 1B and C, and Appendix Fig S3G and H).”

The highest levels observed were in the low two-digit μg/ml range for both antibodies.

“The highest levels observed were in the low two‐digit μg/ml range for both antibodies.”

High expression was obtained over a broad range of molar ratios (heavy:light chain).

“High expression was obtained over a broad range of molar ratios (heavy:light chain) (Appendix Fig S2).”

Constructs for IgG mAbs against rabies glycoprotein G (S057), influenza B hemagglutinin (CR8033), HIV gp120 (VRC01), and human CD20 (rituximab) all revealed strong in vitro expression upon mRNA transfection of BHK cells.

“Constructs for IgG mAbs against rabies glycoprotein G (S057), influenza B hemagglutinin (CR8033; Dreyfus et al, 2012), HIV gp120 (VRC01; Wu et al, 2010), and human CD20 (rituximab) all revealed strong in vitro expression upon mRNA transfection of BHK cells as measured by Western blot analysis and IgG‐specific ELISA (Fig 1E and F, and Appendix Fig S3A–F).”

For VNA-BoNTA and VNA-Stx2, considerable titers were measured as early as 2 h post-injection.

“For VNA‐BoNTA and VNA‐Stx2, considerable titers were measured as early as 2 h post‐injection (Fig 3E and Appendix Fig S7B).”

During the following days, titers slowly decreased with a half-life of approximately 1 week.

“During the following days, titers slowly decreased with a half‐life of approximately 1 week.”

No dose-limiting toxicity was observed up to the doses tested so far.

“nor did we observe any dose‐limiting toxicity.”

Estimated half-lives of VNA serum titers at one to 3 days after treatment were on average 1.5-fold higher than from day 3 on, even without a target-specific mRNA optimization.

“Indeed, estimated half‐lives of VNA serum titers at one to 3 days after treatment were on average 1.5‐fold higher than from day 3 on, even without a target‐specific mRNA optimization.”

Serum half-life for two different proteins turned out to be in the range of 1 week.

“Serum half‐life for two different proteins turned out to be in the range of 1 week.”

Repeated intravenous administration of either 50 or 10 μg of mRNA-LNP for rituximab strongly decelerated or even abolished tumor cell growth.

“repeated intravenous administration of either 50 or 10 μg of mRNA‐LNP for rituximab strongly decelerated or even abolished tumor cell growth.”

All control mice in the BoNT/A experiment died.

“while all control mice died.”

Treatment with recombinant antibody at a dose widely used in mouse studies on rituximab clearly suppressed tumor growth.

“treatment with recombinant antibody at a dose which has been widely used in mouse studies on rituximab clearly suppressed tumor growth.”

Up to the doses tested so far, the dose-response curve for mRNA-mediated antibody expression did not reveal any saturation.

“Secondly, up to the doses tested so far, we found that the dose–response curve for mRNA‐mediated antibody expression did not reveal any saturation”

Mice treated 6 h post-intoxication with VNA-BoNTA mRNA or recombinant VNA-BoNTA displayed moderate clinical signs.

“however, these mice displayed moderate clinical signs.”

Control animals in the Raji lymphoma model all revealed strong tumor cell proliferation and had to be euthanized 17 days after inoculation due to severe symptoms.

“Control animals all revealed strong tumor cell proliferation and had to be euthanized 17 days after inoculation due to severe symptoms (Fig 5B–D).”

• Also stated in: § Prophylaxis and therapy with mRNA‐encoded antibodies in mice · hedged

  “untreated control mice revealed fast tumor progression leading to euthanization after about 17 days.”

Mice treated 6 h post-intoxication with VNA-BoNTA mRNA or recombinant VNA-BoNTA survived.

“Mice treated 6 h post‐intoxication with VNA‐BoNTA mRNA or recombinant VNA‐BoNTA also survived (Fig 4G)”

A fourfold lower dose of anti-rabies mRNA gave rise to just partial protection.

“A fourfold lower dose gave rise to just partial protection.”

The pharmacokinetics data for an anti-rabies antibody appeared to suggest an induction of an ADA response, as about half of the animals revealed accelerated serum clearance after about 2 weeks (Fig 3C and D).

“The pharmacokinetics data for an anti‐rabies antibody indeed appeared to suggest an induction of an ADA response as about half of the animals revealed accelerated serum clearance after about 2 weeks (Fig 3C and D).”

All mice which received the negative control, mRNA-LNP encoding VNA-Stx2, succumbed within 36 h.

“Again, all mice which received the negative control, mRNA‐LNP encoding VNA‐Stx2, succumbed within 36 h.”

Serum clearance maintained its slow initial rate during the whole observation period for a humanized anti-HA antibody (Fig 3D).

“In contrast, serum clearance maintained its slow initial rate during the whole observation period for a humanized anti‐HA antibody (Fig 3D).”

Animals treated with irrelevant antibody mRNA appeared to show delayed tumor growth kinetics.

“Animals treated with irrelevant antibody mRNA appeared to show delayed tumor growth kinetics.”

mRNA half-life in vivo is roughly 15 h.

“we utilized mRNA‐LNPs encoding the short‐lived hormone erythropoietin, suggesting a half‐life of roughly 15 h (Appendix Fig S4B), which is in good accordance with in vitro measurements.”

Antibodies could inhibit rabies infection up to 4 h post-exposure.

“Nevertheless, antibodies could inhibit infection up to 4 h post‐exposure.”

1 out of 12 mice treated with 40 μg of mRNA for the irrelevant anti-influenza mAb survived.

“1 out of 12 mice treated with 40 μg of mRNA for the irrelevant anti‐influenza mAb survived”

All animals receiving just buffer succumbed to rabies infection.

“While all animals receiving just buffer succumbed to rabies infection”

We did not observe any adverse events throughout the present studies.

“We did not observe any adverse events throughout the present studies.”

The individual clearance rates strongly correlated with the development of a humoral response against the anti-rabies antibody.

“Obviously, the individual clearance rates strongly correlated with the development of a humoral response against the anti‐rabies antibody (Appendix Fig S8), thus perfectly explaining the divergent kinetics.”

Animals that received a fourfold lower dose of influenza mRNA showed a survival rate of about 40%.

“animals that received a fourfold lower dose of influenza mRNA again showed a survival rate of about 40%.”

In a second post-exposure rabies challenge experiment, all mice receiving 40 μg of mRNA for anti-rabies mAb survived.

“Again, all mice receiving 40 μg of mRNA for anti‐rabies mAb survived (Fig 4E).”

Full survival with no clinical signs was observed when animals were treated at 2 or 4 h after BoNT/A intoxication with either VNA-BoNTA mRNA or recombinant VNA-BoNTA.

“Full survival with no clinical signs was observed when animals were treated at 2 or 4 h after intoxication with either VNA‐BoNTA mRNA or recombinant VNA‐BoNTA (Appendix Fig S10A and B)”

Histopathology of liver did not reveal any signs of abnormality or inflammation.

“Histopathology of liver, the target organ of mRNA‐LNPs, did not reveal any signs of abnormality or inflammation (Appendix Fig S9).”

This drop of serum titers correlated with elevated ADA levels 4 weeks after treatment (Appendix Fig S8).

“This drop of serum titers correlated with elevated ADA levels 4 weeks after treatment (Appendix Fig S8).”

Protection against death was achieved even with a 6 h post-exposure treatment.

“Protection against death was achieved even with a 6 h post‐exposure treatment.”

In vitro and in vivo experiments revealed efficient expression of functional antibodies from exogenous mRNA.

“In vitro and in vivo experiments revealed efficient expression of functional antibodies from exogenous mRNA.”

Protection was obtained in pre- and post-exposure treatment scenarios.

“Protection was obtained in pre‐ and post‐exposure treatment scenarios.”

In vivo, LNP-mRNA-mediated antibody expression protected mice against diverse biological threats such as virus, toxin, and neoplastic cell growth.

“In vivo, LNP–mRNA‐mediated antibody expression protected mice against diverse biological threats such as virus, toxin, and neoplastic cell growth.”

• Also stated in: § Impact · plain

  “The present study reveals that mRNA‐mediated antibody expression can confer protection against diverse biological threats.”

Half-lives of serum titers were much shorter for VNAs compared to mAbs.

“As expected, half‐lives of serum titers were much shorter for VNAs compared to mAbs.”

The efficacy of mRNA was comparable to recombinant antibody therapy in a particularly challenging post-exposure scenario for intoxication.

“As a consequence, the efficacy of mRNA was comparable to recombinant antibody therapy in a particularly challenging post‐exposure scenario for intoxication.”

mRNA revealed favorable expression kinetics giving rise to immediately elevated antibody serum titers.

“mRNA revealed a favorable expression kinetics giving rise to immediately elevated antibody serum titers.”

The mRNA technology's flexibility was demonstrated by the expression of different antibodies and antibody formats such as classical IgG-based monoclonal antibodies (mAbs) or heavy-chain-only neutralizing agents (VNAs).

“Flexibility of the technology was demonstrated by the expression of different antibodies and antibody formats such as classical IgG‐based monoclonal antibodies (mAbs) or heavy‐chain‐only neutralizing agents (VNAs).”

Passive immunization, by transferring either serum or purified antibodies, is a potent means to confer immediate protection against various threats.

“Hence, passive immunization, by transferring either serum or purified antibodies, is a potent means to confer immediate protection against various threats.”

The present study demonstrates the utility of formulated mRNA as a potent novel technology for passive immunization.

“In conclusion, the present study demonstrates the utility of formulated mRNA as a potent novel technology for passive immunization.”

Neutralizing antibodies are sufficient to prevent dissemination of many diseases within populations.

“It has been demonstrated that neutralizing antibodies are sufficient to prevent dissemination of many diseases within populations (Plotkin, 2010).”

• cites Plotkin, 2010 sourceNot checked — no full text of the source

This bipartite kinetics was confirmed in a second independent study.

“This bipartite kinetics was confirmed in a second independent study.”

mRNA-based antibodies for passive immunization may be produced at competitive costs even in cases where the product is only required in emergencies such as an influenza pandemic.

“Thus, mRNA‐based antibodies for passive immunization may be produced at competitive costs even in cases where the product is only required in emergencies such as an influenza pandemic.”

The nonlinear increase of serum titers with mRNA doses for mAbs is not related to the necessity of correctly assembling heavy and light chains and the separation of both on distinct mRNA molecules.

“However, this effect is not related to the necessity of correctly assembling heavy and light chains and the separation of both on distinct mRNA molecules, since the nonlinearity is equal or even more pronounced for the single‐chain VNA constructs.”

Compared to DNA-based approaches, mRNA benefits from fewer safety issues due to its non-integrative and transient nature.

“Compared to DNA‐based approaches, mRNA benefits from fewer safety issues due to its non‐integrative and transient nature”

• AssumptionRests on an assumption: DNA-based passive immunization suffers from the risk of genomic integration, potentially causing fatal mutations.

Our work establishes the foundation for development of novel passive immunization therapies.

“Thus, our work establishes the foundation for development of novel passive immunization therapies.”

Exogenous mRNA can direct protein expression in vivo.

“Following initial studies in the early 1990s demonstrating that exogenous mRNA can direct protein expression in vivo, mRNA has emerged as a promising drug platform technology in recent years (Wolff et al, 1990; Jirikowski et al, 1992).”

• cites Wolff et al, 1990 sourceNot checked — no full text of the source
• cites Jirikowski et al, 1992 sourceNot checked — no full text of the source

mRNA proved to be an efficient means to express diverse antibodies and antibody formats in vitro.

“Taken together, mRNA proved to be an efficient means to express diverse antibodies and antibody formats in vitro.”

mRNA-mediated mAb expression in vivo efficiently produced functional antibodies.

“Hence, as for in vitro expression, mRNA‐mediated mAb expression in vivo efficiently produced functional antibodies.”

According to in vitro data, the rabies virus enters cells within 20 min after inoculation (Dietzschold et al, 1985).

“According to in vitro data, the virus enters cells within 20 min after inoculation (Dietzschold et al, 1985).”

• cites Dietzschold et al, 1985 sourceNot checked — no full text of the source

mRNA-based antibody expression onset has highly favorable kinetics.

“thereby highlighting the highly favorable kinetics of mRNA‐based antibody expression onset”

mRNA-encoded antibodies appear to represent a viable therapeutic option for various biological threats, including viral infections, intoxication, and cancer.

“In summary, mRNA‐encoded antibodies appear to represent a viable therapeutic option for various biological threats, including (viral) infections, intoxication, and cancer.”

mRNA appears to be at no (substantial) disadvantage compared to DNA with respect to serum levels.

“Of note, mRNA appears to be at no (substantial) disadvantage compared to DNA with respect to serum levels.”

mRNA was at no disadvantage compared to recombinant protein in a post-intoxication setting.

“Taken together, mRNA was at no disadvantage compared to recombinant protein in a post‐intoxication setting”

A further dose escalation appears to be feasible if even higher serum antibody levels are desirable.

“Thus, a further dose escalation appears to be feasible if even higher serum antibody levels are desirable.”

The use of a previously approved design for the various constructs instead of having individually optimized mRNA formats is most likely responsible for the different outcomes.

“Thus, the use of a previously approved design for the various constructs instead of having individually optimized mRNA formats is most likely responsible for the different outcomes.”

Using diverse disease models, mRNA-mediated antibody expression proved capable of providing therapeutic benefit.

“Using diverse disease models, mRNA‐mediated antibody expression proved capable of providing therapeutic benefit.”

mRNA-LNP enables a rapid and strong expression of mRNA-encoded mAbs and VNAs.

“In summary, we could demonstrate that mRNA‐LNP enables a rapid and strong expression of mRNA‐encoded mAbs and VNAs.”

With regard to antibody titers, mRNA appears to be applicable to a broad range of indications.

“Overall, with regard to antibody titers, mRNA appears to be applicable to a broad range of indications.”

Efficacy of the anti-rabies antibody is limited, requiring titers in the upper single digit μg/ml range for full protection.

“On the one hand, this means that efficacy of this specific antibody is limited, at least requiring titers in the upper single digit μg/ml range for full protection.”

Sustained protein availability was not compromised by in situ expression via mRNA.

“Moreover, sustained protein availability was not compromised by in situ expression via mRNA.”

The present data suggest that mRNA-encoded antibodies offer a therapeutic option in humans as well.

“Thus, the present data suggest that mRNA‐encoded antibodies offer a therapeutic option in humans as well.”

The difference in peak expression levels between anti-rabies mAb and BoNTA VNA cannot be simply attributed to distinct antibody designs, since Stx2 VNA expression produced antibody titers at the same level as the anti-rabies mAb.

“Obviously, this difference cannot be simply attributed to the distinct antibody designs, since Stx2 VNA expression produced antibody titers at the same level as the anti‐rabies mAb.”

Survival rates of 0-40% represent the natural variation of spontaneous survival under the challenge conditions used here.

“Hence, survival rates of 0–40% rather appear to represent the natural variation of spontaneous survival under the challenge conditions used here.”

mRNA may be the ideal platform for applications where combination of both passive and active immunization is of advantage or even required, such as for rabies post-exposure prophylaxis.

“In consequence, mRNA may be the ideal platform for applications where combination of both passive and active immunization is of advantage or even required such as for rabies post‐exposure prophylaxis.”

• AssumptionRests on an assumption: Any passive vaccination platform needs to provide effective antibody levels soon after drug administration.

A merging of administration routes for passive and active immunization appears to be possible, if necessary or desirable.

“Therefore, a merging of administration routes for passive and active immunization appears to be possible, if necessary or desirable.”

The findings of the present study suggest mRNA to be a promising novel platform for antibody therapies.

“Taken together, the findings of the present study suggest mRNA to be a promising novel platform for antibody therapies.”

• AssumptionRests on an assumption: Any passive vaccination platform needs to provide effective antibody levels soon after drug administration.

It has been demonstrated that mRNA active vaccination can use both the intramuscular as well as the intravenous route (Petsch et al, 2012; Kranz et al, 2016).

“It has been demonstrated that mRNA active vaccination can use both the intramuscular as well as the intravenous route (Petsch et al, 2012; Kranz et al, 2016).”

• cites Petsch et al, 2012 sourceNot checked — no full text of the source
• cites Kranz et al, 2016 sourceNot checked — no full text of the source

mRNA appears to represent an appropriate platform for antibody expression.

“Thus, mRNA appears to represent an appropriate platform for antibody expression.”

• AssumptionRests on an assumption: Any protein therapy has the inherent risk of inducing an anti-drug antibody (ADA) response which may limit drug efficacy, particularly over time.
• AssumptionRests on an assumption: The probability of an ADA response is especially high for proteins that are foreign to the body.
• AssumptionRests on an assumption: The risk of ADA response may be further increased if the protein is encoded by a nucleic acid which may trigger an innate immune response via diverse cellular sensors.

Here, we present evidence that mRNA can act as an appropriate platform for passive immunization.

“Here, we present evidence that mRNA can act as an appropriate platform for passive immunization.”

• AssumptionRests on an assumption: Any passive vaccination platform needs to provide effective antibody levels soon after drug administration.