Delta infection following vaccination elicits potent neutralizing immunity against the SARS-CoV-2 Omicron

Since the initial detection of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant (B.1.1.529) in November 2021 in South Africa, it has caused a rapid increase in infections globally. The Omicron variant encodes 37 amino acid substitutions in its spike protein, and early reports have provided evidence for extensive immune escape and reduced vaccine effectiveness. We assessed serum neutralizing activity in sera from Delta infection following vaccination of CoronaVac or ZF2001 and Delta infection only against SARS-CoV-2 Wuhan-Hu-1 (WA1), Beta, Delta, and Omicron. We found that sera from Delta infection only could neutralize WA1 and Delta pseudoviruses but nearly completely lost capacity to neutralize Beta and Omicron pseudoviruses. However, Delta infection following vaccination resulted in a significant increase of serum neutralizing activity against WA1, Beta, and Omicron. This study demonstrates that breakthrough infection of Delta in previously vaccinated individuals substantially induced high potency humoral immune response against the Omicron variant and other emerged variants.

Superior immunity that allows neutralization of all SARS-CoV-2 variants of concern develops in COVID-19 convalescents and naïve individuals after three vaccinations

Infection-neutralizing antibody responses after SARS-CoV-2 infection or COVID-19 vaccination are an essential part of antiviral immunity. This immune protection is challenged by the occurrence of SARS-CoV-2 variants of concern (VoCs) with immune escape properties, such as omicron (B.1.1.529) that is rapidly spreading worldwide. Here, we report neutralizing antibody dynamics in a longitudinal cohort of COVID-19 convalescent and naïve individuals vaccinated with mRNA BNT162b2 by quantifying anti-SARS-CoV-2-spike antibodies and determining their avidity and neutralization capacity. A superior infection-neutralizing capacity against all VoCs, including omicron, developed by either two vaccinations of convalescents, or a third vaccination or breakthrough infection of twice-vaccinated naïve individuals. These three consecutive spike antigen exposures resulted in an increasing neutralization capacity per anti-spike antibody unit and were paralleled by stepwise increases in antibody avidity. In conclusion, an infection/vaccination-induced hybrid immunity or a triple immunization induces high-quality antibodies resulting in superior neutralization capacity against VoCs, including omicron.

Effect of Vaccination on Household Transmission of SARS-CoV-2 Delta VOC

The SARS-CoV-2 Delta variant of concern (VOC), which has shown increased transmission compared with previous variants, emerged rapidly globally during the first half of 2021, and became one of the most widespread SARS-CoV-2 variants worldwide. We utilized total population data from 24,693 Danish households with 53,584 potential secondary cases to estimate household transmission of the Delta VOC in relation to vaccination status. We found that the vaccine effectiveness against susceptibility (VES) was 61\% (95\%-CI: 59-63) and that the vaccine effectiveness against transmissibility (VET) was 42\% (95\%-CI: 39-45). We also found that unvaccinated individuals with an infection exhibited a higher viral load (one third of a standard deviation) compared to fully vaccinated individuals with a breakthrough infection. Our results imply that vaccinations reduce susceptibility as well as transmissibility. The results are important for policy makers to select strategies for reducing transmission of SARS-CoV-2.

Timing of Breakthrough Infection Risk After Vaccination Against SARS-CoV-2

Background: Provision of safe and effective vaccines has been a remarkable public health achievement during the SARS-CoV-2 pandemic. The effectiveness and durability of protection of the first two doses of SARS-CoV-2 vaccines is an important area for study, as are questions related to optimal dose combinations and dosing intervals. Methods: We performed a case-cohort study to generate real-world evidence on efficacy of first and second dose of SARS-CoV-2 vaccines, using a population-based case line list and vaccination database for the province of Ontario, Canada between December 2020 and October 2021. Risk of infection after vaccination was evaluated in all laboratory-confirmed vaccinated SARS-CoV-2 cases, and a 2% sample of vaccinated controls, evaluated using survival analytic methods, including construction of Cox proportional hazards models. Vaccination status was treated as a time-varying covariate. Results: First and second doses of SARS-CoV-2 vaccine markedly reduced risk of infection (first dose efficacy 68%, 95% CI 67% to 69%; second dose efficacy 88%, 95% CI 87 to 88%). In multivariable models, extended dosing intervals were associated with lowest risk of breakthrough infection (HR for redosing 0.64 (95% CI 0.61 to 0.67) at 6-8 weeks). Heterologous vaccine schedules that mixed viral vector vaccine first doses with mRNA second doses were significantly more effective than mRNA only vaccines. Risk of infection largely vanished during the time period 4-6 months after the second vaccine dose, but rose markedly thereafter. Interpretation: A case-cohort design provided an efficient means to identify strong protective effects associated with SARS-CoV-2 vaccination, particularly after the second dose of vaccine. However, this effect appeared to wane once more than 6 months had elapsed since vaccination. Heterologous vaccination and extended dosing intervals improved the durability of immune response.

SARS-CoV-2 Vaccine Responses in Individuals with Antibody Deficiency: Findings From The COV-AD Study

Background Vaccination prevents severe morbidity and mortality from COVID-19 in the general population. The immunogenicity and efficacy of SARS-CoV-2 vaccines in patients with antibody deficiency is poorly understood. Objectives COVID in patients with antibody deficiency (COV-AD) is a multi-site United Kingdom study that aims to determine the immune response to SARS-CoV-2 infection and vaccination in patients with primary or secondary antibody deficiency, a population that suffers from severe and recurrent infection and does not respond well to vaccination. Methods Individuals on immunoglobulin replacement therapy or with an IgG less than 4g/L receiving antibiotic prophylaxis were recruited from April 2021. Serological and cellular responses were determined using ELISA, live-virus neutralisation and interferon gamma release assays. SARS-CoV-2 infection and clearance were determined by PCR from serial nasopharyngeal swabs. Results 5.6% (n=320) of the cohort reported prior SARS-CoV-2 infection, but only 0.3% remained PCR positive on study entry. Seropositivity, following two doses of SARS-CoV-2 vaccination, was 54.8% (n=168) compared with 100% of healthy controls (n=205). The magnitude of the antibody response and its neutralising capacity were both significantly reduced compared to controls. Participants vaccinated with the Pfizer/BioNTech vaccine were more likely to be seropositive (65.7% vs 48.0%, p=0.03) and have higher antibody levels compared with the AstraZeneca vaccine (IgGAM ratio 3.73 vs 2.39, p=0.0003). T cell responses post vaccination were demonstrable in 46.2% of participants, were associated with better antibody responses but there was no difference between the two vaccines. Eleven vaccine-breakthrough infections have occurred to date, 10 of them in recipients of the AstraZeneca vaccine. Conclusion SARS-CoV-2 vaccines demonstrate reduced immunogenicity in patients with antibody deficiency with evidence of vaccine breakthrough infection.

Vaccination-infection interval determines cross-neutralization potency to SARS-CoV-2 Omicron after breakthrough infection by other variants

Background The immune profile against SARS-CoV-2 has dramatically diversified due to a complex combination of exposure to vaccines and infection by various lineages/variants, likely generating a heterogeneity in protective immunity in a given population. To further complicate this, the Omicron variant, with numerous spike mutations, has emerged. These circumstances have created the need to assess the potential of immune evasion by the Omicron in individuals with various immune histories. Methods The neutralization susceptibility of the variants including the Omicron and their ancestor was comparably assessed using a panel of plasma/serum derived from individuals with divergent immune histories. Blood samples were collected from either mRNA vaccinees or from those who suffered from breakthrough infections by the Alpha/Delta with multiple time intervals following vaccination. Findings The Omicron was highly resistant to neutralization in fully vaccinated individuals without a history of breakthrough infections. In contrast, robust cross-neutralization against the Omicron were induced in vaccinees that experienced breakthrough infections. The time interval between vaccination and infection, rather than the variant types of infection, was significantly correlated with the magnitude and potency of Omicron-neutralizing antibodies. Conclusions Immune histories with breakthrough infections can overcome the resistance to infection by the Omicron, with the vaccination-infection interval being the key determinant of the magnitude and breadth of neutralization. The diverse exposure history in each individual warrants a tailored and cautious approach to understanding population immunity against the Omicron and future variants. Funding This study was supported by grants from the Japan Agency for Medical Research and Development (AMED).