Susceptibility to SARS-CoV-2 breakthrough infection in those with hybrid immunity is strongly associated with low levels of pre-existing antibody, but the diversity of immune markers associated with protection implies that additional benefits may be conferred by multi-pronged immunity.
Abstract
Background Improved understanding of how variants cause breakthrough infection, despite pre-existing immunity, is needed to advance development of next-generation SARS-CoV-2 vaccines, including those that may provide cross-variant protection or block transmission. SARS-CoV-2 controlled human infection models (CHIMs) may therefore identify correlates of protection and accelerate the development of new interventions. Methods Healthy vaccinated adults aged 18-30 years were inoculated intranasally in a stepwise dose-escalation CHIM with doses from 1x102 TCID50 to 1x106 TCID50 of SARS-CoV-2 Delta variant. Within the 1x106 TCID50 group, participants were selected for serum neutralising antibody titres (NT50) less than or equal to 1:80. Post-inoculation, participants were quarantined for up to 14 days. Outpatient follow-up continued for 12 months. The primary aim was to elicit safe, well-tolerated Delta SARS-CoV-2 breakthrough infection at a rate of over 50%. Findings Forty-six participants were inoculated; 22 during dose-escalation with no resultant infections, and 24 at the highest dose, of whom 18 were screened for low serum neutralising antibodies. Sustained infection with mild-to-moderate symptoms occurred in 33% (6/18) of the sero-selected group, with highly variable viral loads, viral emissions and symptoms. Serum neutralising antibody, anti-N IgG and to a lesser extent, mucosal anti-S IgA and N-specific T cells most strongly predicted protection from virologically-defined infection. Higher neutralisation, serum and nasal anti-N IgG level, and N-specific T cell responses correlated with lower viral load, while baseline nasal anti-S IgA was associated with lower symptom scores. Transient infection was additionally observed in 6 participants and was associated with higher baseline N-specific T cell responses than those that developed sustained infection. Interpretation Susceptibility to SARS-CoV-2 breakthrough infection in those with hybrid immunity is strongly associated with low levels of pre-existing antibody, but the diversity of immune markers associated with protection implies that additional benefits may be conferred by multi-pronged immunity.
Individuals with asymptomatic SARS-CoV-2 infection can unknowingly transmit the virus, yet identifying such subclinical infections in post-vaccinated populations remains challenging. We conducted a longitudinal study of 129 infection-naïve vaccine recipients immunized with various combinations of SARS-CoV-2 spike (S) protein vaccine platforms. Sera were collected before the first dose (v1), at 2 weeks (v7) and 6 months (v8) after the third dose. Taiwan’s first major COVID-19 outbreak occurred between v7 and v8. We measured anti-nucleocapsid (anti-N) and anti-S IgG antibody titers by ELISA and assessed virus-neutralizing activity using live virus and pseudovirus assays. By developing an iterative serial screening method, we identified asymptomatic breakthrough (post-vaccination) infections among unconfirmed cases. Our v7-v8 paired cohort resolved into three distinct groups: confirmed cases (21%), asymptomatic breakthrough infections (17%), and uninfected subjects (62%). In normalized v8 sera, confirmed cases exhibited an anti-S+++ (high) /anti-N+++ (high) phenotype, while uninfected subjects showed an anti-S+ (low)/anti-N+(baseline) phenotype. Statistical analysis validated a distinct asymptomatic group characterized by an antibody profile anti-S++ (intermediate) /anti-N+ (baseline). This approach may enable more accurate estimates of vaccine efficacy and infection prevalence. In a spike-vaccinated population, anti-N antibody is more a potential specific marker for COVID-19 symptomatic disease than an ideal marker for SARS-CoV-2 infection. To our knowledge, this is the first preliminary report of identification of asymptomatic breakthrough infection from a well-vaccinated population using self-matched longitudinal pairs of serum samples.
C. Shih, You-Zhen Liao, Che-Yu Hsu et al.· Journal of Biomedical Scienc...· 0 citations
It is hypothesized that next-generation CoV vaccines incorporating highly conserved SARS-CoV-2 T cell antigens would confer potent, broad, long-lasting cross-protective immunity against multiple VOCs.
Swayam Prakash, N. Dhanushkodi, Afshana Quadiri et al.· npj Vaccines· 0 citations
BACKGROUND
Real-world data studies suggest that the vaccine effectiveness (VE) of a fourth mRNA vaccine dose against SARS-CoV2 infection related hospitalisation wanes after a few months, potentially warranting consideration of additional booster doses.
METHODS
A multi-database cohort study was conducted through the Data Analysis and Real World Interrogation Network (DARWIN EU®) using routinely collected electronic health records from the UK (CPRD GOLD), the Netherlands (IPCI), and Spain (SIDIAP) from January 2021 to June 2023. The study included individuals aged 12 and above, vaccinated with at least three doses. We matched fourth-dose to third-dose vaccinated individuals using a weekly sequential approach, defining the date of the last dose received by the exposed individual as index date. Primary outcomes were SARS-CoV2 infection related death and hospitalisation. Hazard ratios (HR) were estimated using Cox proportional hazard models, with VE defined as the percentage of 1 minus HR. Waning of VE was assessed at monthly intervals.
FINDINGS
A total number of 975,496 matched pairs were identified from the three databases, with a median age of 63-78. The pooled VE of a fourth vaccine dose against SARS-CoV2 infection related death compared to three vaccine doses was 30% (95%CI 9 to 46, I2=0). VE against SARS-CoV2 infection related hospitalisation was 26% (19% to 33%) and 46% (15% to 66%), in Spain (SIDIAP, median follow-up 8 weeks) and Netherlands (IPCI, median follow-up 21 weeks) respectively. VE of a fourth dose started waning at 4-8 weeks after vaccination.
INTERPRETATION
A fourth dose of a mRNA COVID-19 vaccination was effective against SARS-CoV2 infection related death and hospitalisation. However, effectiveness waned over time. Periodic revaccination should be considered, with recommendations regarding booster timing taking into account circulating variants, patterns of viral transmission, and population uptake.
FUNDING
European Medicines Agency.
Xintong Li, N. Mercadé-Besora, Amy Shuk Man Lam et al.· Journal of Infection· 0 citations
Lower humoral immune responses with increasing time after heterologous mRNA booster vaccination in individuals primed with CoronaVac and may inform future booster strategies are suggested.
H. Harapan, A. P. Ayulinda, Qatrunnada Kamil et al.· Acta Tropica· 0 citations
SARS-CoV-2 has evolved into several genetic variants, all bearing mutations that reduce antibody binding and affect vaccine and treatment effectiveness. Updated COVID-19 vaccines, including bivalent formulations (wild type [WT]/BA.1 or WT/BA.5) and more recent monovalent versions targeting emerging variants such as XBB.1.5, JN.1, KP.2 or LP.8.1, were developed to broaden protection. However, immune imprinting may limit the induction of neutralizing antibodies against strains that differ significantly, even after receiving several variant-specific boosters. A deeper understanding of how booster vaccination reshapes antibody specificity remains essential for rational vaccine design. We examined the antibody response to a bivalent WT/BA.5 booster, focusing on antibody levels and neutralization. Serum samples collected before and after a fourth dose of monovalent WT or bivalent (WT/BA.5) mRNA vaccines were compared with sera from individuals after primary WT infections and Omicron BA.1, BA.2, or BA.5 breakthrough infections. We found that both monovalent and bivalent boosters significantly increased IgG and neutralizing antibodies, but breakthrough infections induced broader cross-reactive responses. Depletion experiments revealed that booster-induced immunity was predominantly mediated by cross-reactive antibodies, with the highest levels after breakthrough infections and the lowest after a primary WT infection. These findings provide functional insights into the antibody specificities associated with imprinting effects following variant-adapted booster vaccination.
Iris Medits-Weiss, Dominik Moll, D. Springer et al.· Scientific Reports· 0 citations
