Francis, M. E. | Search bioRxiv

bioRxiv2022

Pre-existing immunity to influenza viruses through infection and/or vaccination leads to viral mutational signatures associated with unique immune responses during a subsequent infection

Our biggest challenge to reducing the burden of seasonal influenza is the constant antigen drift of circulating influenza viruses which then evades the protection of pre-existing immunity. Continual viral infection and influenza vaccination creates a layered immune history in people, however, how host preimmunity interacts with an antigenically divergent virus exposure is poorly understood. Here we investigated the influence of host immune histories on influenza viral mutations. Immune backgrounds were devised in mice similar to what is experienced in people: naive; previously infected (A/FM/1/1947); previously vaccinated (Sanofi quadrivalent vaccine); and previously infected and then vaccinated. Mice were challenged with the heterologous H1N1 strain A/Mexico/4108/2009 to assess protection, viral mutation, and host responses in respect to each immune background by RNAseq. Viral sequences were analyzed for antigenic changes using DiscoTope 2.0 and Immune Epitope Database (IEDB) Analysis Resource NetMHCpan EL 4.1 servers. The mock infected-vaccinated group consistently had the greatest number of viral mutations seen across several viral proteins, HA, NA, NP, and PB1 which was associated with strong antiviral responses and moderate T cell and B cell responses. In contrast, the preimmune-vaccinated mice were not associated with variant emergence and the host profiles were characterized by minimal antiviral immunity but strong T cell, B cell, and NK cell responses. This work suggests that the infection and vaccination history of the host dictates the capacity for viral mutation at infection through immune pressure. These results are important for developing next generation vaccination strategies. ImportanceInfluenza is a continual public health problem. Due to constant virus circulation and vaccination efforts, people have complex influenza immune histories which may impact the outcome of future infections and vaccinations. How immune histories influence the emergence of new variants and the immune pressure stimulated at exposure is poorly understood. Our study addressed this knowledge gap by utilizing mice that are preimmune to influenza viruses and analyzing host responses as well as viral mutations associated with changes in antigenicity. Importantly, we found previous vaccination induced immune responses with moderate adaptive immunity and strong antiviral immunity which was associated with increased mutations in the influenza virus. Interestingly, animals that were previously infected with a heterologous virus and also vaccinated had robust adaptive responses with little to no antiviral induction which was associated with no emergence of viral variants. These results are important for the design of next generation influenza vaccines.

microbiology↗

bioRxiv2019

Influenza preimmunity increases vaccination efficacy by influencing antibody longevity,neutralization activity, and epitope specificity

Influenza virus infections are a recurrent public health problem causing millions of hospitalizations each year despite vaccination efforts. The well-known yearly cycling of influenza viruses is the result of the reciprocal and coevolutionary relationship between the host and virus. Together, from the frequent infections and yearly vaccinations humans build a complex immune history over their lifetimes. Despite the prominence of immune history, vaccines are rarely evaluated in the imprinted (preimmune) host. We developed a ferret model for this purpose where ferrets were imprinted with a sublethal dose of the historical seasonal H1N1 strain A/USSR/90/1977 (USSR/77). A +60 day recovery period was given to build immune memory prior to vaccination with a split virion QIV vaccine. To evaluate protection, the ferrets were challenged with a 2009 H1N1 pandemic virus matching the vaccine antigens. The preimmune-vaccinated ferrets did not experience significant disease during challenge while the naive-vaccinated group were the most severe. Hemagglutination inhibition (HAI) assays showed that preimmune ferrets had a faster and longer antibody response post vaccination for all vaccine antigens compared to minimal HAI responses in the naive-vaccinated group. To investigate the immune mechanisms leading to disease protection in the preimmune ferrets, we performed microneutralization and isotype ELISA assays. Microneutralization suggested preimmune ferrets developed antibodies that were more functional for virus neutralization. Antibody isotype profiling indicated that virus specific antibodies in the preimmune-vaccinated ferrets was dominated by the IgG isotype suggesting B cell maturity and possible plasticity in a pre-existing B cell. Surprisingly, the naive-vaccinated ferrets developed a more severe disease with less virus neutralization suggesting improper immunological processing of vaccine antigens. Together, these results showed the preimmune host had greater responses to vaccination, and the predominant IgG virus specific antibodies suggested a flexible long-lived B cell response. These results are important and should be considered for vaccine design.\n\nAUTHOR SUMMARYThe influenza virus is a significant threat to human health and the economy despite large-scale vaccination efforts. The low effectiveness of the seasonal influenza vaccine is attributed to the frequently mutating virus enabling people to have several influenza virus infections throughout their lifetimes. As people are susceptible to multiple infections, they build a complex immune history. Despite this, vaccines are often not evaluated in animals with an immune history. Here we developed a ferret model that had previously been infected with a historical influenza virus to evaluate vaccine responses to current vaccines. Ferrets were infected with a sublethal does of a historical virus, A/USSR/90/1977, to develop a preimmune background. Preimmune ferrets were vaccinated with the Sanofi quadrivalent influenza vaccine and the antibody responses were investigated after vaccination. Our results showed that preimmune ferrets had a stronger antibody response following vaccination and the antibodies developed were older and better at neutralizing influenza virus at a virus challenge. Clinically, preimmune-vaccinated ferrets developed a milder disease during challenge compared to naive-vaccinated ferrets. This work indicates that the host responses to vaccination are dependent on the host background and that influenza vaccine development and evaluation should take host influenza background into account.

microbiology↗