SARS-CoV-2 variants of concern (VOCs) differentially trigger neutralizing antibodies with variable cross-neutralizing capacity. Here we show that unlike SARS-CoV-2 Omicron BA.1, which triggered neutralizing antibodies with limited cross-reactivity, BA.4/5 infection triggers highly cross-reactive neutralizing antibodies. Cross-reactivity was observed both in the absence of prior vaccination and also in breakthrough infections following vaccination. This suggests that next-generation vaccines incorporating BA.4, which is spreading globally, might result in enhanced neutralization breadth.
The SARS-CoV-2 Omicron variant escapes neutralizing antibodies elicited by vaccines or infection. However, whether Omicron triggers cross-reactive humoral responses to other variants of concern (VOCs) remains unknown. We use plasma from 20 unvaccinated and seven vaccinated individuals infected by Omicron BA.1 to test binding, Fc effector function and neutralization against VOCs. In unvaccinated individuals, Fc effector function and binding antibodies target Omicron and other VOCs at comparable levels. However, Omicron BA.1-triggered neutralization is not extensively cross-reactive for VOCs (14 to 31-fold titer reduction) and we observe 4-fold decreased titers against Omicron BA.2. In contrast, vaccination followed by breakthrough Omicron infection was associated with improved cross-neutralization of VOCs, with titers exceeding 1:2,100. This has important implications for vulnerability of unvaccinated Omicron-infected individuals to reinfection by circulating and emerging VOCs. While Omicron-based immunogens may be adequate boosters, they are unlikely to be superior to existing vaccines for priming in SARS-CoV-2 naive individuals.
The Janssen (Johnson & Johnson) Ad26.COV2.S non-replicating viral vector vaccine has been widely deployed for COVID-19 vaccination programs in resource-limited settings. Here we confirm that neutralizing and binding responses to Ad26.COV2.S vaccination are stable for 6 months post-vaccination, when tested against multiple SARS-CoV-2 variants. Secondly, using longitudinal samples from individuals who experienced clinically mild breakthrough infections 4 to 5 months after vaccination, we show dramatically boosted binding antibodies, Fc effector function and neutralization. These high titer responses are of similar magnitude to humoral immune responses measured in severely ill, hospitalized donors, and are cross-reactive against diverse SARS-CoV-2 variants, including the extremely neutralization resistant Omicron (B.1.1.529) variant that currently dominates global infections, as well as SARS-CoV-1. These data have implications for population immunity in areas where the Ad26.COV2.S vaccine has been widely deployed, but where ongoing infections continue to occur at high levels.
BackgroundAs at end of July 2021, the COVID-19 pandemic has been less severe in sub-Saharan Africa than elsewhere. In Malawi, there have been two subsequent epidemic waves. We therefore aimed to describe the dynamics of SARS-CoV-2 exposure in Malawi. MethodsWe measured the seroprevalence of anti-SARS-CoV-2 antibodies among randomly selected blood donor sera in Malawi from January 2020 to February 2021. In a subset, we also assesed in vitro neutralisation against the original variant (D614G WT) and the Beta variant. FindingsA total of 3586 samples were selected from the blood donor database, of which 2685 (74.9%) were male and 3132 (87.3%) were aged 20-49 years. Of the total, 469 (13.1%) were seropositive. Seropositivity was highest in October 2020 (15.7%) and February 2021 (49.7%) reflecting the two epidemic waves. Unlike the first wave, both urban and rural areas had high seropositivity by February 2021, Balaka (rural, 37.5%), Blantyre (urban, 54.8%), Lilongwe (urban, 54.5%) and Mzuzu (urban, 57.5%). First wave sera showed potent in vitro neutralisation activity against the original variant (78%[7/9]) but not the Beta variant (22% [2/9]). Second wave sera potently neutralised the Beta variant (73% [8/11]). InterpretationThe findings confirm extensive SARS-CoV-2 exposure in Malawi over two epidemic waves with likely poor cross-protection to reinfection from the first on the second wave. Since prior exposure augments COVID-19 vaccine immunity, prioritising administration of the first dose in high SARS-CoV-2 exposure settings could maximise the benefit of the limited available vaccines in Malawi and the region. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWe searched PubMed on August 16, 2021, with no language restrictions, for titles and abstracts published between Jan 1, 2020, and August 16, 2021, using the search terms: "SARS-CoV-2 seroprevalence in Africa"[Title/Abstract]) OR "SARS-CoV-2 seroprevalence in blood donors" [Title/Abstract] OR "SARS-CoV-2 seroprevalence in Malawi", and found 15 records. There are limited SARS-CoV-2 seroprevalence studies in sub Saharan Africa, however the few that are available report high seroprevalence than can be deduced from the respective national reported COVID-19 cases and deaths. Only two published SARS-CoV-2 serosurveys were done on blood donors, from Kenya and Madagascar. Blood donor serosurveys have been recommended by the WHO as an important tool for assessing the spread of SARS-CoV-2 and estimating the burden of COVID-19 pandemic. Added value of this studyUnlike previous SARS-CoV-2 blood donor serosurveys in African populations that were conducted for a maximum period of 9 months, our study covers a full year from January 2020 to February 2021, capturing potential introduction of SARS-CoV-2 into Malawi as well as the two epidemic waves. This study provides evidence against the speculation that SARS-CoV-2 had been circulating more widely in sub-Saharan Africa before the first detected cases. It also provides supporting evidence suggesting that the Beta variant was the likely driver of the second wave that resulted in high SARS-CoV-2 seropositivity in January to February 2021 in Malawi. Implications of all the available evidenceOur results show extensive community transmission of SARS-CoV-2 in Malawi as reflected in the blood donors serosurvey, with almost half the sample population being seropositive for anti-SARS-CoV-2 antibodies by February 2021. This has implications for COVID-19 vaccination policy in sub-Saharan Africa (SSA), where there are limited available vaccine doses. Considering that prior exposure to SARS-CoV-2 augments COVID-19 vaccine immunity, strategies to maximise administration of the first vaccine dose, while waiting for more vaccines to become available, could maximise the benefits of the limited available vaccines in high SARS-CoV-2 exposure settings in SSA such as Malawi.
The Johnson and Johnson Ad26.COV2.S single dose vaccine represents an attractive option for COVID-19 vaccination in resource limited countries. We examined the effect of prior infection with different SARS-CoV-2 variants on Ad26.COV2.S immunogenicity. We compared participants who were SARS-CoV-2 naive with those either infected with the ancestral D614G virus, or infected in the second wave when Beta predominated. Prior infection significantly boosted spike binding antibodies, antibody-dependent cellular cytotoxicity and neutralizing antibodies against D614G, Beta and Delta, however neutralization cross-reactivity varied by wave. Robust CD4 and CD8 T cell responses were induced after vaccination, regardless of prior infection. T cell recognition of variants was largely preserved, apart from some reduction in CD8 recognition of Delta. Thus, Ad26.COV2.S vaccination following infection may result in enhanced protection against COVID-19. The impact of the infecting variant on neutralization breadth after vaccination has implications for the design of second-generation vaccines based on variants of concern.
