Recovery from infection or robust vaccine responses could elicit an immune response that protects the individual from subsequent encounters with the similar pathogen, however in the case of SARS-CoV-2 repeat infection with variants of concern (VoC) has become commonplace despite highly effective vaccines. Neutralizing antibodies that block viral entry at the receptor binding domain (RBD) are key to limiting infection, however SARS-CoV-2 is actively evolving, VoC to undermine this defense and related viruses in Bats and Pangolins may present future spill over threats. It would be ideal if we could elicit a lot of cross-reactive antibodies that can recognize variants from vaccination. The immune response to SARS-CoV-2 is shaped by the type of exposure we have encountered, by vaccine type (mRNA or inactivated whole virion) or combination of vaccines, time since infection, and infection with distant viruses (SARS-CoV from 2003) or related variants (Omicron). An in-depth investigation of the reactive antibodies induced during these scenarios provides us information on the potency of the neutralizing antibodies for ideal vaccination strategies to combat variants and future pandemic threats and the development of broad-spectrum universal vaccines.
In a collaborative study led by Dr. Sophie Valkenburg from the University of Hong Kong, we investigated the antibody breadth from different SARS-CoV-2 exposures and vaccinations with collaborators from Hong Kong and Guangzhou, using a multiplex surrogate virus neutralization tests (sVNTs) developed by Prof. Linfa Wang and Chee Wah Tan at Duke-NUS, Singapore. Here, we found that infection+vaccination synergistically improved the breadth and magnitude of neutralizing antibodies especially with mRNA vaccines and to a limited extent with inactivated vaccines. SARS survivors from 2003 who received two doses of BNT162b2, was a combination that outperformed all the other scenarios in terms of both magnitude and breadth of recognition by the antibodies. This finding supports the idea that antigenic diversity introduced by a distantly related strain should be considered for the design of the vaccination and chimeric vaccine derived from different lineages may provide optimal breadth and magnitude of neutralizing activity against the viruses. Indeed, chimeric SARS vaccines are in clinical development with promising results for wide antibody responses. What is also worth pointing out is that even Coronavac, an inactivated vaccines, improved reactivity to both VoC and sarbecovirus when it was given to infected individuals or as an initial priming. Overall, vaccination after infection still provides substantial benefit to our SARS-CoV-2 immunity, as the SARS-CoV-2 infection number keeps going up unexpected immunological advances from hybrid immunity may be obtained. As for the order and type of vaccine we receive,we also determine the breadth of our SARS-type antibody response, with mRNA vaccines outperforming inactivated vaccines as a third booster. In contrast, inactivated vaccine as a booster cannot augment mRNA elicited antibody responses. Yet, inactivated vaccine priming has benefits for cellular immunity based on our other studies on the same group of people.
Although the neutralizing antibody breadth to most SARS-type viruses was improved significantly in these aforementioned groups, the cross-reactive neutralizing antibodies to Omicron variant that emerged in December 2021 are still limited, even in individuals who had Omicron-breakthrough infection. Thus, highlighting the efficiency of Omicron to evade neutralizing antibody recognition and that its emergence stemmed from immune selective pressure. By design, our immune system consists of multiple layers of barriers. Each of these layers are imperfect and required combination of these barriers to protect us from COVID-19. Whilst we observed a significant loss of neutralizing antibodies against Omicron, cellular immunity induced during vaccination (or mucosal cellular immunity induced during infection) helps to prevent most people from severe disease.
Based on the breadth of antibodies now established by various routes of exposure, especially by mRNA vaccination and high rates of SARS-CoV-2 infection, our antibody arsenal is broadened should SARS-CoV-3 ever try and emerge.
Acknowledgements: Written with help from Chee Wah Tan and Sophie Valkenburg. Image made with Biorender.