Antigenic evolution of SARS-CoV-2 in immunocompromised hosts

The apparent lack of antigenic evolution by the Delta variant (B.1.617.2) of SARS-CoV-2 during the COVID-19 pandemic is puzzling. The combination of increasing immune pressure due to the rollout of vaccines and a relatively high number of infections following the relaxation of non-pharmaceutical interventions should have created perfect conditions for immune escape variants to evolve from the Delta lineage. Instead, the Omicron variant (B.1.1.529), which is hypothesised to have evolved in an immunocompromised individual, is the first major variant to exhibit significant immune escape following vaccination programmes and is set to become globally dominant in 2022. Here, we use a simple mathematical model to explore possible reasons why the Delta lineage did not exhibit antigenic evolution and to understand how and when immunocompromised individuals affect the emergence of immune escape variants. We show that when the pathogen does not have to cross a fitness valley for immune escape to occur, immunocompromised individuals have no qualitative effect on antigenic evolution (although they may accelerate immune escape if within-host evolutionary dynamics are faster in immunocompromised individuals). But if a fitness valley exists between immune escape variants at the between-host level, then persistent infections of immunocompromised individuals allow mutations to accumulate, therefore facilitating rather than simply speeding up antigenic evolution. Our results suggest that better global health equality, including improving access to vaccines and treatments for individuals who are immunocompromised (especially in lower- and middle-income countries), may be crucial to preventing the emergence of future immune escape variants of SARS-CoV-2.

Antigenic evolution of human influenza H3N2 neuraminidase is constrained by charge balancing

As one of the main influenza antigens, neuraminidase (NA) in H3N2 virus has evolved extensively for more than 50 years due to continuous immune pressure. While NA has recently emerged as an effective vaccine target, biophysical constraints on the antigenic evolution of NA remain largely elusive. Here, we apply combinatorial mutagenesis and next-generation sequencing to characterize the local fitness landscape in an antigenic region of NA in six different human H3N2 strains that were isolated around 10 years apart. The local fitness landscape correlates well among strains and the pairwise epistasis is highly conserved. Our analysis further demonstrates that local net charge governs the pairwise epistasis in this antigenic region. In addition, we show that residue coevolution in this antigenic region is correlated with the pairwise epistasis between charge states. Overall, this study demonstrates the importance of quantifying epistasis and the underlying biophysical constraint for building a model of influenza evolution.

Vaccine nationalism and the dynamics and control of SARS-CoV-2

Vaccines provide powerful tools to mitigate the enormous public health and economic costs that the ongoing SARS-CoV-2 pandemic continues to exert globally, yet vaccine distribution remains unequal among countries. To examine the potential epidemiological and evolutionary impacts of ‘vaccine nationalism’, we extend previous models to include simple scenarios of stockpiling between two regions. In general, when vaccines are widely available and the immunity they confer is robust, sharing doses minimizes total cases across regions. A number of subtleties arise when the populations and transmission rates in each region differ, depending on evolutionary assumptions and vaccine availability. When the waning of natural immunity contributes most to evolutionary potential, sustained transmission in low access regions results in an increased potential for antigenic evolution, which may result in the emergence of novel variants that affect epidemiological characteristics globally. Overall, our results stress the importance of rapid equitable vaccine distribution for global control of the pandemic.

Antigenic evolution of human influenza H3N2 neuraminidase is constrained by charge balancing

As one of the main influenza antigens, neuraminidase (NA) in H3N2 virus has evolved extensively for more than 50 years due to continuous immune pressure. While NA has emerged as an effective vaccine target recently, biophysical constraints on the antigenic evolution of NA remain largely elusive. Here, we apply deep mutational scanning to characterize the local fitness landscape in an antigenic region of NA in six different human H3N2 strains that were isolated around 10 years apart. The local fitness landscape correlates well among strains and the pairwise epistasis is highly conserved. Our analysis further demonstrates that local net charge governs the pairwise epistasis in this antigenic region. In addition, we show that residue coevolution in this antigenic region can be predicted by charge states and pairwise epistasis. Overall, this study demonstrates the importance of quantifying epistasis and the underlying biophysical constraint for building a predictive model of influenza evolution.

Antibodies elicited by mRNA-1273 vaccination bind more broadly to the receptor binding domain than do those from SARS-CoV-2 infection

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with mutations in key antibody epitopes has raised concerns that antigenic evolution could erode adaptive immunity elicited by prior infection or vaccination. The susceptibility of immunity to viral evolution is shaped in part by the breadth of epitopes targeted by antibodies elicited by vaccination or natural infection. To investigate how human antibody responses to vaccines are influenced by viral mutations, we used deep mutational scanning to compare the specificity of polyclonal antibodies elicited by either two doses of the mRNA-1273 COVID-19 vaccine or natural infection with SARS-CoV-2. The neutralizing activity of vaccine-elicited antibodies was more targeted to the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein compared to antibodies elicited by natural infection. However, within the RBD, binding of vaccine-elicited antibodies was more broadly distributed across epitopes compared to infection-elicited antibodies. This greater binding breadth means that single RBD mutations have less impact on neutralization by vaccine sera compared to convalescent sera. Therefore, antibody immunity acquired by natural infection or different modes of vaccination may have a differing susceptibility to erosion by SARS-CoV-2 evolution.

Vaccine nationalism and the dynamics and control of SARS-CoV-2

Vaccines provide powerful tools to mitigate the enormous public health and economic costs that the ongoing SARS-CoV-2 pandemic continues to exert globally, yet vaccine distribution remains unequal between countries. To examine the potential epidemiological and evolutionary impacts of 'vaccine nationalism', we extend previous models to include simple scenarios of stockpiling. In general, we find that stockpiling vaccines by countries with high availability leads to large increases in infections in countries with low vaccine availability, the magnitude of which depends on the strength and duration of natural and vaccinal immunity. Additionally, a number of subtleties arise when the populations and transmission rates in each country differ depending on evolutionary assumptions and vaccine availability. Furthermore, the movement of infected individuals between countries combined with the possibility of increases in viral transmissibility may greatly magnify local and combined infection numbers, suggesting that countries with high vaccine availability must invest in surveillance strategies to prevent case importation. Dose-sharing is likely a high-return strategy because equitable allocation brings non-linear benefits and also alleviates costs of surveillance (e.g. border testing, genomic surveillance) in settings where doses are sufficient to maintain cases at low numbers. Across a range of immunological scenarios, we find that vaccine sharing is also a powerful tool to decrease the potential for antigenic evolution, especially if infections after the waning of natural immunity contribute most to evolutionary potential. Overall, our results stress the importance of equitable global vaccine distribution.

Genetic and antigenic evolution of H1 swine influenza A viruses isolated in Belgium and the Netherlands from 2014 through 2019

Surveillance of swine influenza A viruses (swIAV) allows timely detection and identification of new variants with potential zoonotic risks. In this study, we aimed to identify swIAV subtypes that circulated in pigs in Belgium and the Netherlands between 2014 and 2019, and characterize their genetic and antigenic evolution. We subtyped all isolates and analyzed hemagglutinin sequences and hemagglutination inhibition assay data for H1 swIAV, which were the dominant HA subtype. We also analyzed whole genome sequences (WGS) of selected isolates. Out of 200 samples, 89 tested positive for swIAV. swIAV of H1N1, H1N2 and H3N2 subtypes were detected. Analysis of WGS of 18 H1 swIAV isolates revealed three newly emerged genotypes. The European avian-like H1 swIAV (lineage 1C) were predominant and accounted for 47.2% of the total isolates. They were shown to evolve faster than the European human-like H1 (1B lineage) swIAV, which represented 27% of the isolates. The 2009 pandemic H1 swIAV (lineage 1A) accounted for only 5.6% of the isolates and showed divergence from their precursor virus. These results point to the increasing divergence of swIAV and stress the need for continuous surveillance of swIAV.