Diminished neutralization responses towards SARS-CoV-2 Omicron VoC after mRNA or vector-based COVID-19 vaccinations

SARS-CoV-2 variants accumulating immune escape mutations provide a significant risk to vaccine-induced protection. The novel variant of concern (VoC) Omicron (B.1.1.529) has the largest number of amino acid alterations in its Spike protein to date. Thus, it may efficiently escape recognition by neutralizing antibodies, allowing breakthrough infections in convalescent and vaccinated individuals. We analyzed neutralization activity of sera from individuals after vaccination with all mRNA-, vector- or heterologous immunization schemes currently available in Europe by in vitro neutralization assay at peak response towards SARS-CoV-2 B.1, Omicron, Beta and Delta pseudotypes and also provide longitudinal follow-up data from BNT162b2 vaccinees. All vaccines apart from Ad26.CoV2.S showed high levels of responder rates (93-100%) towards SARS-CoV-2 wild-type, but some reductions in neutralizing Beta and Delta VoC pseudotypes. The novel Omicron variant had the biggest impact, both in terms of response rates and neutralization titers. Only mRNA-1273 showed a 100% response rate to Omicron and induced the highest level of neutralizing antibody titers, followed by heterologous prime-boost approaches. Homologous BNT162b2 vaccination or vector-based AZD1222 or Ad26.CoV2.S performed less well with peak responder rates of 33%, 50% and 9%, respectively. However, Omicron responder rates in BNT162b2 recipients were maintained in our six month longitudinal follow-up indicating that individuals with cross-protection against Omicron maintain it over time. Overall, our data strongly argues for urgent booster doses in individuals who were previously vaccinated with BNT162b2, or a vector-based immunization scheme.

Human serum from SARS-CoV-2 vaccinated and COVID-19 patients shows reduced binding to the RBD of SARS-CoV-2 Omicron variant in comparison to the original Wuhan strain and the Beta and Delta variants

The COVID-19 pandemic is caused by the betacoronavirus SARS-CoV-2. In November 2021, the Omicron variant was discovered and classified as a variant of concern (VOC). Omicron shows substantially more mutations in the spike protein than any previous variant, mostly in the receptor binding domain (RBD). We analyzed the binding of the Omicron RBD to the human ACE2 receptor (hACE2) and the ability of human sera from COVID-19 patients or vaccinees in comparison to Wuhan, Beta or Delta RBDs variants. All RBDs were produced in insect cells. RBD binding to hACE2 was analyzed by ELISA and microscale thermophoresis (MST). Similarly, sera from 27 COVID-19 patients, 58 fully vaccinated individuals and 16 booster recipients were titrated by ELISA on the fixed RBDs from the original Wuhan strain, Beta, Delta and Omicron VOC. Surprisingly, the Omicron RBD showed a weaker binding to ACE2 compared to Beta and Delta, arguing that improved ACE2 binding is not a likely driver of Omicron evolution. Serum antibody titers were significantly lower against Omicron RBD compared to the original Wuhan strain. However, a difference of 2.5 times was observed in RBD binding while in other studies the neutralization of Omicron SARS-CoV-2 was reduced by a magnitude of 10x and more. These results indicate an immune escape focused on neutralizing antibodies. The reduced binding of sera to Omicron RBD adds evidence that current vaccination protocols may be less efficient against the Omicron variant.

SARS-CoV-2 seroprevalence in Germany - a population based sequential study in five regions

Prevalence of SARS-CoV-2 antibodies is an essential indicator to guide measures. Few population-based estimates are available in Germany. We determine seroprevalence allowing comparison between regions, time points, socio-demographic and health-related factors. MuSPAD is a sequential multi-local seroprevalence study. We randomly recruited adults in five counties with differing cumulative SARS-CoV-2 incidence July 2020 -February 2021. Serostatus was determined using Spike S1-specific IgG ELISA. We determined county-wise proportions of seropositivity. We assessed underestimation of infections, county and age specific infection fatality risks, and association of seropositivity with demographic, socioeconomic and health factors. We found seroprevalence of 2.4 % (95%CI: 1.8-3.1%) for Reutlingen in June 2020 (stage 1) which increased to 2.9% (95%CI: 2.1-3.8%) in October (stage 2), Freiburg stage 1 1.5% (95% CI: 1.1-2.1%) vs. 2.5% (95%CI: 1.8-3.4%), Aachen stage 1 2.3% (95% CI: 1.7-3.1%) vs. 5.4% (95%CI: 4.4-6.6%), Osnabruck 1.3% (95% CI: 1.0-1.9%) and Magdeburg in Nov/Dec 2020. 2.4% (95%CI 1.9-3.1%). Number needed to quarantine to prevent one infection was 8.2. The surveillance detection ratio (SDR) between number of infections based on our results and number reported to health authorities ranged from 2.5-4.5. Participants aged 80+ had lower SDR. Infection fatality estimates ranged from 0.2-2.4%. Lower education was associated with higher, smoking with lower seropositivity. Seroprevalence remained low until December 2020 with high underdetection. The second wave from November 2020 to February 2021 resulted in additional 2-5% of the population being infected. Detected age specific differences of SDR should be taken into account in modelling and forecasting COVID-19 morbidity. FundingThe Helmholtz Association, European Unions Horizon 2020 research and innovation programme [grant number 101003480] and intramural funds of the Helmholtz Centre for infection (HZI). HighlightsO_ST_ABSEvidence before this studyC_ST_ABSSeroepidemiological surveys on SARS-CoV-2 are a useful tool to track the transmission during the epidemic. We searched PubMed/the pre-print server medRxiv and included web-based reports from German health organizations using the keywords "seroprevalence", "SARS-CoV-2", "Germany" and similar other English and German terms in the period from January 1st, 2020 until March 2021. We identified 30 published studies in Germany which mostly report low SARS-CoV-2 seroprevalence (<5%). Most of these surveys were so-called hotspot studies which assessed seroprevalence after localized outbreaks or examined seroprevalence of specific population groups such as e.g. medical staff. Few studies are either population-based or blood donor-based, but do not allow comparisons between regions. To date, we only consider the Corona sub-study of the Rhineland study similar to MuSPAD. It reports a low SARS-CoV-2 seroprevalence (46/4755; 0.97%; 95% CI: 0.72-1.30). Based on this, almost the entire German population remained susceptible to a SARS-CoV-2 infection by the end of 2020. Added value of this studyWe provide the first comprehensive, high-precision multi-region population-based SARS-CoV-2 seroprevalence study with representative sampling following the WHO protocol in Germany. By measuring SARS-CoV-2 IgG, we explore immunity at regional and national level over time. We also assess risk factors and sample each region twice, which permits to monitor seroprevalence progression throughout the epidemic in different exemplary German regions. Implications of all the available evidenceOur results show low seroprevalence (<3%) until Mid-December 2020 in all regions. While estimates in Reutlingen, Aachen, Freiburg and Osnabruck reflect low seroprevalence mostly after the first wave, the survey in Magdeburg cumulatively already represents the beginning of the second wave. The number needed to quarantine to prevent one infection was 8.2 in our study. We also show that for the first wave reported infections reflected overall around 25% of those actually infected rising to 40-50% in the second wave. A slightly raised infection risk could be shown for persons with lower education.