Immune imprinting revealed by SARS-CoV-2 Omicron infection prior to vaccination (preprint)

Immune imprinting or original antigenic sin (OAS) originally referred to a phenomenon of suboptimal immune response to a repeat exposure to a virus that was antigenically distinct from the original virus infection. OAS has been implicated in higher mortality in young people during the 2009-10 H1N1 pandemic where the elderly (H1N1 exposure in childhood) appeared relatively well protected compared to younger individuals whose first influenza infection was not H1N1. Immune imprinting is part of a rapid recall system and is highly effective against a slowly evolving virus (drifting) but not antigenically shifting viruses such as influenza and SARS CoV-2. As predicted by OAS, suboptimal neutralization responses to the highly divergent SARS-COV-2 lineage Omicron have been observed in animal models and individuals previously vaccinated with primary course of ancestral (Wu-1) vaccine. Due to the rapid scale up of vaccine before emergence of the antigenically distinct Omicron variant, it is unknown whether immunological imprinting for occurs in the context of SARS-COV-2 infection itself. We longitudinally assessed humoral responses to primary two dose Ad26.COV2.S Wu-hu-1 based vaccination in a Nigerian population following the global emergence of Omicron. At study entry in Jan 2023, we found 93% and 58% of pre-vaccination participants previously exposed to ancestral Wu-1 and Omicron virus respectively by anti-N IgG and anti-receptor binding domain (RBD) IgG Wu-1 and Omicron -specific antibodies. In participants with no evidence of prior exposure to Omicron, neutralisation against Wu-1 was significantly higher than Omicron variants as expected. However, serum neutralisation titres in participants who were anti-RBD Omicron IgG positive were paradoxically 2-fold lower for Omicron BA.1 as compared to Wu-1. This is clear evidence for imprinted immunity from the ancestral pre-omicron lineage viruses, and remarkably these old responses to Wu-1 were able to dominate over more recent, likely multiple, Omicron lineage infections. Furthermore, in these participants with prior exposure to Omicron and evidence of imprinting, we observed that further Omicron infection and Wu-1 based vaccine was associated with boosting of responses across variants with equalisation of neutralisation titres for Wu-1 and Omicron variants. However, omicron responses did not surpass ancestral responses, suggesting persistence of imprinting and only partial mitigation. Although neutralization responses at high titres were observed post dose 1 vaccination against ancestral and Omicron variants BA.1, BA.2, BA.4 in nearly all participants, neutralisation against the highly immune evasive XBB recombinant variant remained substantially lower, with a second vaccine dose providing very modest boosting. These data highlight immune imprinting against SARS-CoV-2 prior to vaccination and its persistence thereafter. In present day unvaccinated populations where serum neutralisation responses to pre-Omicron variants dominate, use of an omicron variant based vaccine should be used in preference to Wu-1 based vaccine to override imprinting and provide broader protection for vulnerable populations such as the elderly or those with compromised immunity.

Ecologic correlation between underlying population level morbidities and COVID-19 case fatality rate among countries infected with SARS-CoV-2 (preprint)

Background: The ongoing Coronavirus disease 2019 (COVID-19) pandemic is unprecedented in scope. High income countries (HIC) seemingly account for the majority of the mortalities considering that these countries have screened more persons. Low middle income countries (LMIC) countries may experience far worse mortalities considering the existence of a weaker health care system and the several underlying population level morbidities. As a result, it becomes imperative to understand the ecological correlation between critical underlying population level morbidities and COVID-19 case fatality rates (CFR). Method: This is an ecological study using data on COVID-19 cases, prevalence of COPD, prevalence of tobacco use, adult HIV prevalence, quality of air and life expectancy. We plotted a histogram, performed the Shapiro-Wilk normality test and used spearman correlation to assess the degree of correlation between COVID-19 case fatality rate (CFR) and other covariates mentioned above. Result: As at the 31st of March 2020, there were a total of 846,281 cases of COVID-19 from 204 countries and a global case fatality rate of 5% (range 0% to 29%). Angola and Sudan both had the highest CFR of 29%, while Italy had the highest number of deaths (i.e. 12,428) as at 31st of March 2020. Adult HIV prevalence has a significant but weak negative correlation with CFR (correlation coefficient = - 0.24, p value =0.01) while all the other variables have positive correlation with CFR due to COVID-19 though not statistically significant. Of the 204 countries analyzed, only 11 countries (i.e. 5%) had complete datasets across all 5 population level morbidities (i.e. prevalence of COPD, prevalence of tobacco use, life expectancy, quality of air, and adult HIV prevalence variables). Correlations of CFR from these 11 countries were similar to that from the 204 countries except for the correlation with quality of air and prevalence of tobacco use. Conclusion: While we interpret our data with caution given the fact that this is an ecological study, our findings suggest that population level factors such as prevalence of COPD, prevalence of tobacco use, life expectancy and quality of air are positively correlated with CFR from COVID-19 but, adult HIV prevalence has a weak and negative correlation with COVID-19 CFR and would require extensive research.