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The hemagglutinin (HA) stem region is a major target of universal influenza vaccine efforts owing to the presence of highly conserved epitopes across multiple influenza A virus (IAV) strains and subtypes. To explore the potential impact of vaccine-induced immunity targeting the HA stem, we examined the fitness effects of viral escape from stem-binding broadly neutralizing antibodies (stem-bnAbs). Recombinant viruses containing each individual antibody escape substitution showed diminished replication compared to wild-type virus, indicating that stem-bnAb escape incurred fitness costs. A second-site mutation in the HA head domain (N129D; H1 numbering) reduced the fitness effects observed in primary cell cultures and likely enabled the selection of escape mutations. Functionally, this putative permissive mutation increased HA avidity for its receptor. These results suggest a mechanism of epistasis in IAV, wherein modulating the efficiency of attachment eases evolutionary constraints imposed by the requirement for membrane fusion. Taken together, the data indicate that viral escape from stem-bnAbs is costly but highlights the potential for epistatic interactions to enable evolution within the functionally constrained HA stem domain.

The hemagglutinin (HA) stem region is a major target of universal influenza vaccine efforts owing to the presence of highly conserved epitopes across multiple influenza A virus (IAV) strains and subtypes. To explore the potential impact of vaccine-induced immunity targeting the HA stem, we examined the fitness effects of viral escape from stem-binding broadly neutralizing antibodies (stem-bnAbs). Recombinant viruses containing each individual antibody escape substitution showed diminished replication compared to wild-type virus, indicating that stem-bnAb escape incurred fitness costs. A second-site mutation in the HA head domain (N129D; H1 numbering) reduced the fitness effects observed in primary cell cultures and likely enabled the selection of escape mutations. Functionally, this putative permissive mutation increased HA avidity for its receptor. These results suggest a mechanism of epistasis in IAV, wherein modulating the efficiency of attachment eases evolutionary constraints imposed by the requirement for membrane fusion. Taken together, the data indicate that viral escape from stem-bnAbs is costly but highlights the potential for epistatic interactions to enable evolution within the functionally constrained HA stem domain. [ABSTRACT FROM AUTHOR]

The repeated emergence of SARS-CoV-2 escape mutants from host immunity has obstructed the containment of the current pandemic and poses a serious threat to humanity. Prolonged infection in immunocompromised patients has received increasing attention as a driver of immune escape, and accumulating evidence suggests that viral genomic diversity and emergence of immune-escape mutants are promoted in immunocompromised patients. However, because immunocompromised patients comprise a small proportion of the host population, whether they have a significant impact on antigenic evolution at the population level is unknown. We consider an evolutionary epidemiological model that combines antigenic evolution and epidemiological dynamics. Applying this model to a heterogeneous host population, we study the impact of immunocompromised hosts on the evolutionary dynamics of pathogen antigenic escape from host immunity. We derived analytical formulae of the speed of antigenic evolution in heterogeneous host populations and found that even a small number of immunocompromised hosts in the population significantly accelerates antigenic evolution. Our results demonstrate that immunocompromised hosts play a key role in viral adaptation at the population level and emphasize the importance of critical care and surveillance of immunocompromised hosts. [ABSTRACT FROM AUTHOR]

BA.2.86, a recently described sublineage of SARS-CoV-2 Omicron, contains many mutations in the spike gene. It appears to have originated from BA.2 and is distinct from the XBB variants responsible for many infections in 2023. The global spread and plethora of mutations in BA.2.86 has caused concern that it may possess greater immune-evasive potential, leading to a new wave of infection. Here, we examine the ability of BA.2.86 to evade the antibody response to infection using a panel of vaccinated or naturally infected sera and find that it shows marginally less immune evasion than XBB.1.5. We locate BA.2.86 in the antigenic landscape of recent variants and look at its ability to escape panels of potent monoclonal antibodies generated against contemporary SARS-CoV-2 infections. We demonstrate, and provide a structural explanation for, increased affinity of BA.2.86 to ACE2, which may increase transmissibility., Competing Interests: Declaration of interests G.R.S. sits on the GSK Vaccines Scientific Advisory Board, consults for AstraZeneca, and is a founder member of RQ Biotechnology. D.I.S. consults for AstraZeneca. Oxford University holds intellectual property related to SARS-CoV-2 mAbs discovered in G.R.S.’s laboratory. S.J.D. is a scientific advisor to the Scottish Parliament on COVID-19., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Live attenuated influenza vaccines (LAIV) induce CD8+ T lymphocyte responses that play an important role in killing virus-infected cells. Despite the relative conservation of internal influenza A proteins, the epitopes recognized by T cells can undergo drift under immune pressure. The internal proteins of Russian LAIVs are derived from the master donor virus A/Leningrad/134/17/57 (Len/17) isolated 60 years ago and as such, some CD8+ T cell epitopes may vary between the vaccine and circulating wild-type strains. To partially overcome this issue, the nucleoprotein (NP) gene of wild-type virus can be incorporated into LAIV reassortant virus, along with the HA and NA genes. The present study compares the human CD8+ T cell memory responses to H3N2 LAIVs with the Len/17 or the wild-type NP using an in vitro model.

Currently, SARS-CoV-2 causing coronavirus disease 2019 (COVID-19) is responsible for one of the most deleterious pandemics of our time. The interaction between the ACE2 receptors at the surface of human cells and the viral Spike (S) protein triggers the infection, making the receptor-binding domain (RBD) of the SARS-CoV-2 S-protein a focal target for the neutralizing antibodies (Abs). Despite the recent progress in the development and deployment of vaccines, the emergence of novel variants of SARS-CoV-2 insensitive to Abs produced in response to the vaccine administration and/or monoclonal ones represent a potential danger. Here, we analyzed the diversity of neutralizing Ab epitopes and assessed the possible effects of single and multiple mutations in the RBD of SARS-CoV-2 S-protein on its binding affinity to various antibodies and the human ACE2 receptor using bioinformatics approaches. The RBD-Ab complexes with experimentally resolved structures were grouped into four clusters with distinct features at sequence and structure level. The performed computational analysis indicates that while single amino acid replacements in RBD may only cause partial impairment of the Abs binding, moreover, limited to specific epitopes, the variants of SARS-CoV-2 with multiple mutations, including some which were already detected in the population, may potentially result in a much broader antigenic escape. Further analysis of the existing RBD variants pointed to the trade-off between ACE2 binding and antigenic escape as a key limiting factor for the emergence of novel SAR-CoV-2 strains, as the naturally occurring mutations in RBD tend to reduce its binding affinity to Abs but not to ACE2. The results provide guidelines for further experimental studies aiming to identify high-risk RBD mutations that allow for an antigenic escape.

Virus evolution shapes the epidemiological patterns of infectious disease, particularly via evasion of population immunity. At the individual level, host immunity itself may drive viral evolution towards antigenic escape. Using compartmental SIR-style models with imperfect vaccination, we allow the probability of immune escape to differ in vaccinated and unvaccinated hosts. As the relative contribution to selection in these different hosts varies, the overall effect of vaccination on the antigenic escape pressure at the population level changes. We find that this relative contribution to escape is important for understanding the effects of vaccination on the escape pressure and we draw out some fairly general patterns. If vaccinated hosts do not contribute much more than unvaccinated hosts to the escape pressure, then increasing vaccination always reduces the overall escape pressure. In contrast, if vaccinated hosts contribute significantly more than unvaccinated hosts to the population level escape pressure, then the escape pressure is maximised for intermediate vaccination levels. Past studies find only that the escape pressure is maximal for intermediate levels with fixed extreme assumptions about this relative contribution. Here we show that this result does not hold across the range of plausible assumptions for the relative contribution to escape from vaccinated and unvaccinated hosts. We also find that these results depend on the vaccine efficacy against transmission, particularly through the partial protection against infection. This work highlights the potential value of understanding better how the contribution to antigenic escape pressure depends on individual host immunity. • Population immunity can select for pathogen strains that evape host immunity. • The weight in the escape pressure from cases in the vaccinated may be high or low. • We define a parameter to capture this weight, relative to that from the unvaccinated. • Vaccination affects population-level escape differently depending on this parameter. • Vaccine efficacy also matters for escape, especially protection against infection. [ABSTRACT FROM AUTHOR]

Currently, SARS-CoV-2 causing coronavirus disease 2019 (COVID-19) is responsible for one of the most deleterious pandemics of our time. The interaction between the ACE2 receptors at the surface of human cells and the viral Spike (S) protein triggers the infection, making the receptor-binding domain (RBD) of the SARS-CoV-2 S-protein a focal target for the neutralizing antibodies (Abs). Despite the recent progress in the development and deployment of vaccines, the emergence of novel variants of SARS-CoV-2 insensitive to Abs produced in response to the vaccine administration and/or monoclonal ones represent a potential danger. Here, we analyzed the diversity of neutralizing Ab epitopes and assessed the possible effects of single and multiple mutations in the RBD of SARS-CoV-2 S-protein on its binding affinity to various antibodies and the human ACE2 receptor using bioinformatics approaches. The RBD-Ab complexes with experimentally resolved structures were grouped into four clusters with distinct features at sequence and structure level. The performed computational analysis indicates that while single amino acid replacements in RBD may only cause partial impairment of the Abs binding, moreover, limited to specific epitopes, the variants of SARS-CoV-2 with multiple mutations, including some which were already detected in the population, may potentially result in a much broader antigenic escape. Further analysis of the existing RBD variants pointed to the trade-off between ACE2 binding and antigenic escape as a key limiting factor for the emergence of novel SAR-CoV-2 strains, as the naturally occurring mutations in RBD tend to reduce its binding affinity to Abs but not to ACE2. The results provide guidelines for further experimental studies aiming to identify high-risk RBD mutations that allow for an antigenic escape. [ABSTRACT FROM AUTHOR]

Influenza virus epidemics are caused when seasonal influenza viruses (i.e., those circulating in humans) acquire mutations in the antigenic sites of the viral hemagglutinin (HA) protein that prevent the antibodies present in people from binding to the virus and blocking virus interaction with cellular receptors. To date, vaccination is the best protective option against seasonal influenza viruses. Because influenza viruses frequently acquire mutations in their antigenic sites, vaccine viruses need to be updated regularly. Here, we present an experimental system that allows the simulation of influenza virus evolution in the test tube. By using this system, we can identify antigenic variants that may emerge among natural influenza viruses in the near future. This information would help in the selection and prioritization of variants for vaccine production.