Dose-dependent effects of recombinant spike protein-based vaccination on SARS-CoV-2 evolutionary dynamics and the emergence of variants in hamster models
Aug 2026· Journal of General Virology· Vol 107· 0 citations· 41 references
Medicine
TL;DR
Investigating the evolutionary dynamics of the SARS-CoV-2 Delta variant in hamsters immunized with varying doses of a full-length spike protein vaccine indicates that heterogeneous vaccine-induced immune pressure can shape intra-host SARS-CoV-2 evolution in a dose-dependent and host-specific manner and highlights the potential role of partial immunity and increased iSNVs in the upper respiratory tract in driving the emergence of putative immune-evasive viral variants.
Abstract
Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has continued to circulate globally through the persistent emergence of novel variants. Vaccination has been regarded as one of the selective environments that can influence SARS-CoV-2 evolution by exerting immune pressure. This study investigated the evolutionary dynamics of the SARS-CoV-2 Delta variant in hamsters immunized with varying doses of a full-length spike protein vaccine, potentially reflecting the heterogeneous levels of immunity. In hamster models, higher vaccine doses prevented viral replication in the lungs but only partially suppressed replication in the nasal passages. After excluding intra-host single-nucleotide variants (iSNVs) detected in non-vaccinated controls, a negative binomial model adjusting for read depth revealed a significant vaccine dose-dependent increase in iSNV occurrence in the Spike, ORF1a, ORF1b and ORF3a genes in nasal samples and positive selection signals were predominantly observed in the highest vaccine dose group. The iSNVs were observed in diverse and distinct combinations that were unique to each individual, reflecting host-specific intra-host mutation patterns. Some aa substitutions detected in at least two individuals in the vaccinated group were more frequently observed in the Omicron variant. In silico analyses incorporating individual-specific iSNVs demonstrated that reduced binding affinity to class 1 and 3 neutralizing antibodies was observed exclusively in variants identified from certain vaccinated individuals. In conclusion, these findings indicate that heterogeneous vaccine-induced immune pressure can shape intra-host SARS-CoV-2 evolution in a dose-dependent and host-specific manner and highlight the potential role of partial immunity and increased iSNVs in the upper respiratory tract in driving the emergence of putative immune-evasive viral variants.
It is shown that a Wuhan-lineage-based multi-antigen VLP vaccine can provide cross-protection against an antigenically divergent SARS-CoV-2 variant that is not fully explained by detectable serum neutralizing activity alone, suggesting the importance of integrated immune responses involving humoral, cellular, and local immune mechanisms.
Seung-Ji Kim, Howon Kim, Seung-Eun Son et al.· Vaccine· 0 citations
A combined experimental and computational characterization of SARS-CoV-2 variant-specific neutralisation across infection, vaccination and hybrid immunity-driven cohorts is provided, offering a hypothesis-generating framework to contextualize observed differences in antibody responses and epitope recognition across variants.
Jyoti Sawant, Ajit Patil, Madhuri Thakar et al.· Frontiers in Immunology· 0 citations
SARS-CoV-2 spike—based vaccines control COVID-19, yet vaccine-associated enhanced respiratory disease (VAERD) after breakthrough infection remains a concern. We previously reported Th2/Th17-skewed VAERD in hACE2 mice, however, the mechanisms, durability, and effects of vaccine types and routes in this process are unclear and will be investigated here.
Wild-type mice received spike protein plus alum/CpG and were challenged with MA10 strain 14 days or 7 months post-boost. Parallel cohorts received intramuscular (IM) mRNA vaccines (Comirnaty or Spikevax) and were challenged at 7 months. Splenocytes were restimulated with spike peptide subpools to map Th2/Th17-associated epitopes. B cell or ITK deficient mice were used to define signaling requirements. We also used model antigen ovalbumin (OVA) as a control to test whether the observed Th2/Th17 phenotype is uniquely associated with intranasal spike following IM subunit vaccination. To further assess booster safety, IM mRNA vaccinated mice were boosted with intramuscular mRNA vaccine or intranasal Ad5-Spike.
Despite protection, adjuvanted protein vaccination caused severe lung pathology with CD4+ T infiltration and elevated Th2/Th17 cytokines, persisting to 7 months. mRNA vaccines did not induce Th2/Th17-associated VAERD at delayed challenge. Th2/Th17-linked epitopes localized to S1, and both B cells and ITK signaling were required for pulmonary inflammation. Compared with OVA, intranasal spike after intramuscular adjuvanted vaccination recruited additional lung Th17 cells. For boosting, intramuscular mRNA was markedly safer than intranasal Ad5-Spike, which triggered robust Th2/Th17 inflammation.
VAERD risk can persist long after vaccination and depends on platform and delivery route. Intramuscular mRNA vaccines show superior safety, while spike contains epitopes capable of driving Th2- and Th17-mediated pathology, highlighting the need to refine spike antigens and booster strategies for durable, safe protection.
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Vaccines and Immunotherapy (VAC)
Tianyi Zhang, Nicholas Magazine, Lamis El-Baz et al.· Journal of Immunology· 0 citations
PURPOSE
The COVID-19 pandemic has witnessed the rapid evolution of the SARS-CoV-2 virus, resulting in the emergence of multiple variants with mutations in critical regions of the spike protein, notably in the receptor binding domain. These mutations can lead to immune evasion and breakthrough (BT) infections, even in the vaccinated individuals. While previous studies have documented various mutations, there is a limited understanding of these mutations in different epitopes and their influence on the vaccine elicited immune response.
METHODS
Neutralizing antibodies were detected using Plaque reduction neutralization test and peptide enzyme linked immunosorbent assay was standardized to identify possible epitopes contributing to immune escape. We used GraphPad Prism 9.5.0 (525) for analysis. Results were significant at p < 0.05.
RESULTS
In this study, we observed that individuals with hybrid immunity, defined as immunity derived from both the natural infection and vaccination, exhibit significantly higher levels of neutralizing antibodies than individuals who had been solely vaccinated with COVISHIELD. Consequently, we highlight the substantial differences in the reactivity of neutralizing antibodies against the Wuhan, Delta, and Omicron variants. Our findings indicate that individuals who have recovered from COVID-19 and /or who experienced BT infections, showed stronger reactivity toward the conserved peptides than individuals vaccinated with no prior exposure.
CONCLUSIONS
COVISHIELD induced antibodies effectively neutralized original Wuhan strain but showed reduced neutralization against Delta and Omicron due to mutations in specific epitopes within their spike proteins. Mutations in variant specific epitopes can lead to evasion of the virus, emphasizing the importance of targeting linear region epitopes as critical binding sites.
P. Das, G. Sapkal, Pragya D. Yadav et al.· Indian Journal of Medical Mi...· 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
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