RESUMO
The emergence of SARS-CoV-2 Variants of Concern (VOCs) with mutations in key neutralizing antibody epitopes threatens to undermine vaccines developed against the pandemic founder variant (Wu-Hu-1). Widespread vaccine rollout and continued transmission are creating a population that has antibody responses of varying potency to Wu-Hu-1. Against this background, it is critical to assess the outcomes of subsequent immunization with variant antigens. It is not yet known whether heterotypic vaccine boosts would be compromised by original antigenic sin, where pre-existing responses to a prior variant dampen responses to a new one, or whether the primed memory B cell repertoire would bridge the gap between Wu-Hu-1 and VOCs. Here, we show that a single adjuvanted dose of receptor binding domain (RBD) protein from VOC 501Y.V2 (B.1.351) drives an extremely potent neutralizing antibody response capable of cross-neutralizing both Wu-Hu-1 and 501Y.V2 in rhesus macaques previously immunized with Wu-Hu-1 spike protein. Passive immunization with plasma sampled following this boost protected K18-hACE2 mice from lethal challenge with a 501Y.V2 clinical isolate, whereas only partial protection was afforded by plasma sampled after two Wu-Hu-1 spike immunizations.
RESUMO
The outbreak and spread of SARS-CoV-2 (Severe Acute Respiratory Syndrome coronavirus 2), the cause of coronavirus disease 2019 (COVID-19), is a current global health emergency and a prophylactic vaccine is needed urgently. The spike glycoprotein of SARS-CoV-2 mediates entry into host cells, and thus is a target for neutralizing antibodies and vaccine design. Here we show that adjuvanted protein immunization with SARS-CoV-2 spike trimers, stabilized in prefusion conformation 1, results in potent antibody responses in mice and rhesus macaques with neutralizing antibody titers orders of magnitude greater than those typically measured in serum from SARS-CoV-2 seropositive humans. Neutralizing antibody responses were observed after a single dose, with exceptionally high titers achieved after boosting. Furthermore, neutralizing antibody titers elicited by a dose-sparing regimen in mice were similar to those obtained from a high dose regimen. Taken together, these data strongly support the development of adjuvanted SARS-CoV-2 prefusion-stabilized spike protein subunit vaccines.
RESUMO
Serological studies are critical for understanding pathogen-specific immune responses and informing public health measures1,2. Here, we evaluate tandem IgM, IgG and IgA responses in a cohort of individuals PCR+ for SARS-CoV-2 RNA (n=105) representing different categories of disease severity, including mild and asymptomatic infections. All PCR+ individuals surveyed were IgG-positive against the virus spike (S) glycoprotein. Elevated Ab levels were associated with hospitalization, with IgA titers, increased circulating IL-6 and strong neutralizing responses indicative of intensive care status. Additional studies of healthy blood donors (n=1,000) and pregnant women (n=900), sampled weekly during the initial outbreak in Stockholm, Sweden (weeks 14-25, 2020), demonstrated that anti-viral IgG titers differed over 1,000-fold between seroconverters, highlighting the need for careful evaluation of assay cut-offs for individual measurements and accurate estimates of seroprevalence (SP). To provide a solution to this, we developed probabilistic machine learning approaches to assign likelihood of past infection without setting an assay cut-off, allowing for more quantitative individual and population-level Ab measures. Using these tools, that considered responses against both S and RBD, we report SARS-CoV-2 S-specific IgG in 6.8% of blood donors and pregnant women two months after the peak of spring COVID-19 deaths, with the SP curve and country death rate following similar trajectories.
