Hybrid immunity and vaccine Imprinting: Powerful defenses against Omicron reinfection

To date, the ongoing coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), has claimed more than 6.94 million lives worldwide.

Study: Humoral immune response to omicron infection in long-term Wuhan-Hu-1-imprinted population. Image Credit: visualstock / Shutterstock.com

*Important notice: Research Square publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Background

In contrast to prior recommendations, the recent World Health Organization (WHO) guidance indicated no need for annual booster COVID-19 vaccination for low-risk populations. This updated WHO guidance has triggered a debate on the effectiveness of regular booster vaccination, particularly because of the lack of impressive serum neutralization against SARS-CoV-2 Omicron sub-variants.

The abrupt withdrawal of COVID-19 booster recommendations could also be due to incomplete evidence regarding the persistence and effectiveness of natural infection-elicited immune protection against re-infection caused by emerging variants with different antigenic characteristics.

The majority of studies have indicated that prior infection of Wuhan-Hu-1(WH1), which is the ancestral SARS-CoV-2 strain, and WH1-based vaccination have weakened humoral immune responses to Oubsequent omicron infection. These findings are consistent with immune imprinting in influenza virus infection.

Antigenic cartography studies have demonstrated that antigenic distances between SARS-CoV-2 variants and Omicron sub-variants were only of 103-fold change in neutralization titer levels. Thus, as compared to influenza infection, SARS-CoV-2 infection manifests smaller imprinting effects.

Most of the world population was exposed to SARS-CoV-2 antigens through WH1-based vaccines. As a result, a new study under review at Nature Portfolio and currently posted to the Research Square preprint server evaluates the effects of long-term WH1 imprinting on the humoral immune response to an antigenically distant SARS-CoV-2 variant to determine the maximal imprinting effects in the current SARS-CoV-2 variant landscape. 

About the study

The Hubei province of China, which was the main epicenter of the first COVID-19 outbreak in the world, successfully avoided all pre-Omicron variants due to the implementation of strict public health measures. Most people in Hubei were vaccinated with several rounds of WH1-based COVID-19 vaccines; therefore, the majority of this population was exclusively WH1 imprinted.

Hubei experienced a population-wide Omicron outbreak in December 2022, with about 90% of the population infected by the BF.7 sub-variant and its derivates. Scientists took the opportunity of this sweeping outbreak to study immune imprinting in re-infected participants.

The study cohort comprised WH1-infected participants from Xiangyang City of Hubei province. Study participants reinfected with the Omicron variant provided serum samples two months following the infection. Some of the participants were vaccinated with three doses of whole-inactivated virus (WIV) vaccines.

Serum samples collected from WH1-infected and triple-vaccinated participants at three to four months before Omicron infection were used as pre-infection controls.

Other cohorts from the same region were studied. One cohort included vaccinated participants, whereas another cohort contained unvaccinated participants.

Pre- and post-Omicron infection serum samples from the vaccinated and unvaccinated cohorts were obtained. Importantly, all participants did not have any history of immunological disorders or were under any medication that could affect the immune system.

Humoral immune responses were measured using pseudovirus neutralization assays, which were based on non-replicative vesicular stomatitis viruses (VSV) pseudotyped with spike proteins of WH1, Omicron BF.7, BQ.1.1, or XBB.1.5.

Study findings

The current study used pre-and post-Omicron infection sera from an exclusively WH1-imprinted population to determine long-term and long antigenic distance immune imprinting on the humoral immune system. Based on the pseudovirus neutralization assays, an increase in WH1 and Omicron sub-variants neutralization was observed in WH1 imprinting as compared to naïve sera. 

Mechanistically, antibody feedback limited the magnitude of WH1 back-boost through antibody diversity enhancement. In addition, antigenic seniority caused a rapid upregulation of Omicron neutralization titers by recalling cross-reactive B-cells upon Omicron infection.

Only hybrid WH1 imprinting marginally reduced forward neutralization breadth without affecting the overall neutralization titers after Omicron infection.

Importantly, the imprinting effects collectively increased the protection levels against reinfection. Therefore, it could be beneficial to support immune imprinting for humoral immunity.

Conclusions

The current study supports the WHO recommendation against the COVID-19 booster vaccination in low-risk populations. In fact, the study findings strongly indicate that Omicron infection will confer immune protection in imprinted populations.

However, SARS-CoV-2 variants with more antigenic drift will induce immune protection less effectively, irrespective of the imprinting status. The effect of immune imprinting depends on the quality and quantity of cross-reactive antibodies.

Taken together, long-term WH1 immune imprinting enhances the humoral immune response against Omicron infection with negligible adverse effects, thereby protecting against reinfection. In contrast to the findings of previous studies, the current study concluded that immune imprinting is a beneficial mechanism.

*Important notice: Research Square publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.