Vaccination decreases the risk of influenza A virus reassortment but not genetic variation in pigs
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Curated by eLife
Evaluation Summary:
Vaccines are a major influenza control strategy in swine, but perform sub-optimally and are under-utilized. The manuscript describes a detailed genetic characterization of influenza virus variants in vaccinated versus unvaccinated pigs. The results indicate that viral reassortment, which is an important process yielding new strange of importance to man and animals, may be less common in pigs that have been vaccinated against influenza.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Abstract
Although vaccination is broadly used in North American swine breeding herds, managing swine influenza is challenging primarily due to the continuous evolution of influenza A virus (IAV) and the ability of the virus to transmit among vaccinated pigs. Studies that have simultaneously assessed the impact of vaccination on the emergence of IAV reassortment and genetic variation in pigs are limited. Here, we directly sequenced 28 bronchoalveolar lavage fluid (BALF) samples collected from vaccinated and unvaccinated pigs co-infected with H1N1 and H3N2 IAV strains, and characterized 202 individual viral plaques recovered from 13 BALF samples. We identified 54 reassortant viruses that were grouped in 17 single and 16 mixed genotypes. Notably, we found that prime-boost vaccinated pigs had less reassortant viruses than nonvaccinated pigs, likely due to a reduction in the number of days pigs were co-infected with both challenge viruses. However, direct sequencing from BALF samples revealed limited impact of vaccination on viral variant frequency, evolutionary rates, and nucleotide diversity in any IAV coding regions. Overall, our results highlight the value of IAV vaccination not only at limiting virus replication in pigs but also at protecting public health by restricting the generation of novel reassortants with zoonotic and/or pandemic potential.
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Evaluation Summary:
Vaccines are a major influenza control strategy in swine, but perform sub-optimally and are under-utilized. The manuscript describes a detailed genetic characterization of influenza virus variants in vaccinated versus unvaccinated pigs. The results indicate that viral reassortment, which is an important process yielding new strange of importance to man and animals, may be less common in pigs that have been vaccinated against influenza.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)
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Reviewer #1 (Public Review):
The authors performed a detailed genetic characterization of influenza virus variants in vaccinated versus unvaccinated pigs. A major strength of the paper is that the challenge was done via a more or less natural route, by comingling seeder pigs infected with H1N1 and H3N2 virus with the vaccinated groups. Another strength is the relatively large size of the study (70 animals). On the other hand, even this large number of animals still does not allow a very robust assessment (statistically) of the impact of vaccination on reassortment generation at the level of individual pigs. Nevertheless, vaccination reduced the number of reassortant viruses detected upon plaque purification. Vaccination had limited effect on natural selection of other genetic variants (SNVs). This is an important conclusion, as it seems …
Reviewer #1 (Public Review):
The authors performed a detailed genetic characterization of influenza virus variants in vaccinated versus unvaccinated pigs. A major strength of the paper is that the challenge was done via a more or less natural route, by comingling seeder pigs infected with H1N1 and H3N2 virus with the vaccinated groups. Another strength is the relatively large size of the study (70 animals). On the other hand, even this large number of animals still does not allow a very robust assessment (statistically) of the impact of vaccination on reassortment generation at the level of individual pigs. Nevertheless, vaccination reduced the number of reassortant viruses detected upon plaque purification. Vaccination had limited effect on natural selection of other genetic variants (SNVs). This is an important conclusion, as it seems that vaccination provides an ability to reduce the genetic diversification of swine influenza viruses.
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Reviewer #2 (Public Review):
Influenza A viruses evolve rapidly in US swine, generating novel reassortants that also occasionally infect humans (e.g., H3N2v). The virus is not well controlled in US swine herds, because of the difficulty of designing vaccines that protect against the full diversity of strains. This group and others have done prior work examining different prime-boost strategies to improve the effectiveness of swine influenza vaccines. Here, the authors extend that work by examining the potential for vaccination to blunt the evolution of the virus. Seeder pigs experimentally infected with H1N1 or H3N2 influenza A viruses were co-housed with vaccinated and unvaccinated pigs. The study finds that H1N1 and H3N2 viruses readily coinfect pigs, generating a large number of reassortants over a relatively short time period, and …
Reviewer #2 (Public Review):
Influenza A viruses evolve rapidly in US swine, generating novel reassortants that also occasionally infect humans (e.g., H3N2v). The virus is not well controlled in US swine herds, because of the difficulty of designing vaccines that protect against the full diversity of strains. This group and others have done prior work examining different prime-boost strategies to improve the effectiveness of swine influenza vaccines. Here, the authors extend that work by examining the potential for vaccination to blunt the evolution of the virus. Seeder pigs experimentally infected with H1N1 or H3N2 influenza A viruses were co-housed with vaccinated and unvaccinated pigs. The study finds that H1N1 and H3N2 viruses readily coinfect pigs, generating a large number of reassortants over a relatively short time period, and possibly fewer reassortants in animals administered the prime-boost regimen.
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Reviewer #3 (Public Review):
The authors attempt to track the effect vaccination can have upon viral evolution within the swine host. This is important because novel viruses emerging from animal hosts have the ability to spark the next influenza pandemic.
The paper presents data showing pigs receiving two doses of vaccine had fewer reassortant viruses than non-vaccinated pigs. This is an interesting finding in the context of controlling the genetic diversity of influenza A virus in swine. The study is using samples generated in a previous study (doi.org/10.1186/s13567-020-00810-z). It is unclear how the samples that were used in the present study were selected from the previous study, which introduces significant concerns about selection bias.
The present study does not discuss the homology between vaccine and challenge strains. Readers …
Reviewer #3 (Public Review):
The authors attempt to track the effect vaccination can have upon viral evolution within the swine host. This is important because novel viruses emerging from animal hosts have the ability to spark the next influenza pandemic.
The paper presents data showing pigs receiving two doses of vaccine had fewer reassortant viruses than non-vaccinated pigs. This is an interesting finding in the context of controlling the genetic diversity of influenza A virus in swine. The study is using samples generated in a previous study (doi.org/10.1186/s13567-020-00810-z). It is unclear how the samples that were used in the present study were selected from the previous study, which introduces significant concerns about selection bias.
The present study does not discuss the homology between vaccine and challenge strains. Readers have to refer to Table 2 in the parent paper to find the data. Upon closer examination, at least one of the components of every prime-boost treatment had a vaccine with >95% amino acid homology to a challenge virus. Furthermore, it appears that 25% of the sequenced BALF samples were collected from animals that received at least one dose of an autogenous vaccine that was 99.1% homologous to the H3 challenge virus. With the estimation of antigenic distance, it is hard to predict exactly how protective each vaccine would have been. It is very hard to know if the prime-boost strategy or similarity between the vaccine strains and challenge virus is truly responsible for the observed results.
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