Post by Nadica (She/Her) on Aug 11, 2024 6:28:16 GMT
Mapping SARS-CoV-2 antigenic relationships and serological responses - Published Oct 6, 2023
Editor’s summary
The SARS-CoV-2 pandemic was marked by waves of new strains of virus differing in virulence and immune reactivity. The advent of each new variant of concern brought more human casualties and waves of onerous quarantine measures. To map the evolutionary trajectory of the variants, Wilks et al. obtained sera from people who had been vaccinated or infected with a range of variants of concern and applied antigenic cartography to visualize structural changes in the virus. The authors observed changes in immunodominance and immune escape depending on the variant that had infected the patient or after vaccination. Such analysis has implications for variant risk assessment and for selecting the next candidate vaccine strains that will confer the highest protection. —Caroline Ash
Structured Abstract
INTRODUCTION
Vaccination has greatly reduced the disease burden of SARS-CoV-2. However, since late 2020, variants have emerged that are able to escape immunity from vaccination and previous infections, including B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), and B.1.1.529 (Omicron and its descendants). In combination with vaccination, infections with different variants form the basis of current population immunity against SARS-CoV-2.
RATIONALE
Understanding the antigenic relationships among SARS-CoV-2 variants, the substitutions that cause antigenic change, and how the immune response is shaped by previous infections, is crucial for understanding the evolution of the virus, determining whether new variants avoid neutralization from antibodies induced by current vaccines, and evaluating the need for vaccine updates.
To this end, we analyzed patterns of neutralization and cross-reactivity among a panel of 21 SARS-CoV-2 variants and 15 groups of human sera obtained from individuals after primary infection with one of 10 different variants or after D614G or B.1.351 vaccination. First, we sought to understand patterns of cross-reactivity and response breadth in postvaccination responses 4 weeks and >3 months after second or third vaccine doses. Then, we used antigenic cartography to visualize antigenic relationships between 21 SARS-CoV-2 variants and experimentally test point mutations to investigate the drivers of the antigenic changes observed in the antigenic map. Lastly, we investigated how serological reactivity postinfection relates to the primary-exposure variant.
RESULTS
Quantifying changes in cross-reactivity and response breadth after vaccination, our results show the largest increase between 4 weeks and >3 months after a second dose. In particular, we found that the main short-term effect of the third vaccination was to boost the magnitude of a response that had already become more cross-reactive rather than to generate significant additional breadth of cross-reactivity.
Using antigenic cartography, we inferred and subsequently experimentally tested our inference that antigenic differences among pre-Omicron variants are primarily caused by substitutions at spike-protein positions 417, 452, 484, and 501 (see figure, top). The experimental effect of these substitutions was largely consistent with those inferred from the map.
We also found that sensitivity to these substitutions varied greatly between individuals infected with different variants. These differences are consistent with substantial changes in immunodominance of different spike regions, depending on the variant an individual was first exposed to and the amino acid present at these positions in the eliciting variant (see figure, bottom). For example, whereas sera of individuals exposed to D614G, B.1.1.7, and B.1.617.2 variants are sensitive to changes at position 484, sera of individuals exposed to B.1.351 and P.1 are not.
CONCLUSION
Our results provide a comprehensive analysis of the antigenic variation between SARS-CoV-2 variants and the development of the immune response after infection or vaccination. The large antigenic effect of a small number of substitutions in the receptor-binding domain (RBD) of SARS-CoV-2 is similar to the pattern observed for seasonal influenza viruses, for which major antigenic changes are often associated with single or double substitutions. These substitutions in the SARS-CoV-2 RBD not only allow the virus to escape from preexisting immunity but also influence the regions of the spike protein that the immune response targets. Depending on their infection history, different individuals can thus be sensitive to substitutions in different regions of the spike protein. As individuals increasingly experience multiple infections, choosing vaccine immunogens on the basis of immunodominance considerations may be an important aspect in ensuring high vaccine efficacy across populations with different patterns of preexisting immunity.
Editor’s summary
The SARS-CoV-2 pandemic was marked by waves of new strains of virus differing in virulence and immune reactivity. The advent of each new variant of concern brought more human casualties and waves of onerous quarantine measures. To map the evolutionary trajectory of the variants, Wilks et al. obtained sera from people who had been vaccinated or infected with a range of variants of concern and applied antigenic cartography to visualize structural changes in the virus. The authors observed changes in immunodominance and immune escape depending on the variant that had infected the patient or after vaccination. Such analysis has implications for variant risk assessment and for selecting the next candidate vaccine strains that will confer the highest protection. —Caroline Ash
Structured Abstract
INTRODUCTION
Vaccination has greatly reduced the disease burden of SARS-CoV-2. However, since late 2020, variants have emerged that are able to escape immunity from vaccination and previous infections, including B.1.351 (Beta), P.1 (Gamma), B.1.617.2 (Delta), and B.1.1.529 (Omicron and its descendants). In combination with vaccination, infections with different variants form the basis of current population immunity against SARS-CoV-2.
RATIONALE
Understanding the antigenic relationships among SARS-CoV-2 variants, the substitutions that cause antigenic change, and how the immune response is shaped by previous infections, is crucial for understanding the evolution of the virus, determining whether new variants avoid neutralization from antibodies induced by current vaccines, and evaluating the need for vaccine updates.
To this end, we analyzed patterns of neutralization and cross-reactivity among a panel of 21 SARS-CoV-2 variants and 15 groups of human sera obtained from individuals after primary infection with one of 10 different variants or after D614G or B.1.351 vaccination. First, we sought to understand patterns of cross-reactivity and response breadth in postvaccination responses 4 weeks and >3 months after second or third vaccine doses. Then, we used antigenic cartography to visualize antigenic relationships between 21 SARS-CoV-2 variants and experimentally test point mutations to investigate the drivers of the antigenic changes observed in the antigenic map. Lastly, we investigated how serological reactivity postinfection relates to the primary-exposure variant.
RESULTS
Quantifying changes in cross-reactivity and response breadth after vaccination, our results show the largest increase between 4 weeks and >3 months after a second dose. In particular, we found that the main short-term effect of the third vaccination was to boost the magnitude of a response that had already become more cross-reactive rather than to generate significant additional breadth of cross-reactivity.
Using antigenic cartography, we inferred and subsequently experimentally tested our inference that antigenic differences among pre-Omicron variants are primarily caused by substitutions at spike-protein positions 417, 452, 484, and 501 (see figure, top). The experimental effect of these substitutions was largely consistent with those inferred from the map.
We also found that sensitivity to these substitutions varied greatly between individuals infected with different variants. These differences are consistent with substantial changes in immunodominance of different spike regions, depending on the variant an individual was first exposed to and the amino acid present at these positions in the eliciting variant (see figure, bottom). For example, whereas sera of individuals exposed to D614G, B.1.1.7, and B.1.617.2 variants are sensitive to changes at position 484, sera of individuals exposed to B.1.351 and P.1 are not.
CONCLUSION
Our results provide a comprehensive analysis of the antigenic variation between SARS-CoV-2 variants and the development of the immune response after infection or vaccination. The large antigenic effect of a small number of substitutions in the receptor-binding domain (RBD) of SARS-CoV-2 is similar to the pattern observed for seasonal influenza viruses, for which major antigenic changes are often associated with single or double substitutions. These substitutions in the SARS-CoV-2 RBD not only allow the virus to escape from preexisting immunity but also influence the regions of the spike protein that the immune response targets. Depending on their infection history, different individuals can thus be sensitive to substitutions in different regions of the spike protein. As individuals increasingly experience multiple infections, choosing vaccine immunogens on the basis of immunodominance considerations may be an important aspect in ensuring high vaccine efficacy across populations with different patterns of preexisting immunity.