Clinico-Genomic Analysis Reiterates Mild Symptoms Post-vaccination Breakthrough: Should We Focus on Low-Frequency Mutations?

Abstract

Vaccine development against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been of primary importance to contain the ongoing global pandemic. However, studies have demonstrated that vaccine effectiveness is reduced and the immune response is evaded by variants of concern (VOCs), which include Alpha, Beta, Delta, and, the most recent, Omicron. Subsequently, several vaccine breakthrough (VBT) infections have been reported among healthcare workers (HCWs) due to their prolonged exposure to viruses at healthcare facilities. We conducted a clinico-genomic study of ChAdOx1 (Covishield) VBT cases in HCWs after complete vaccination. Based on the clinical data analysis, most of the cases were categorized as mild, with minimal healthcare support requirements. These patients were divided into two sub-phenotypes based on symptoms: mild and mild plus. Statistical analysis showed a significant correlation of specific clinical parameters with VBT sub-phenotypes. Viral genomic sequence analysis of VBT cases revealed a spectrum of high- and low-frequency mutations. More in-depth analysis revealed the presence of low-frequency mutations within the functionally important regions of SARS-CoV-2 genomes. Emphasizing the potential benefits of surveillance, low-frequency mutations, D144H in the N gene and D138Y in the S gene, were observed to potentially alter the protein secondary structure with possible influence on viral characteristics. Substantiated by the literature, our study highlights the importance of integrative analysis of pathogen genomic and clinical data to offer insights into low-frequency mutations that could be a modulator of VBT infections.

COVID-19 in non-hospitalised adults caused by either SARS-CoV-2 sub-variants Omicron BA.1, BA.2, BA.5 or Delta associates with similar illness duration, symptom severity and viral kinetics, irrespective of vaccination history

“…The remaining 460 episodes, across 433 individuals, were then analysed (Table 1). These individuals had the same age distribution (median 39 years [IQR 31 -49], as the whole Legacy study (40 years [31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47][48][49][50]), and were gender matched to Legacy (68 vs 68% female). Symptom questionnaires were completed for 432/460 episodes (94%).…”

“…It is also important to emphasise that given the observational nature of our study, the sequential spread of Omicron BA.1 and BA.2 in the United Kingdom, and the rapid expansion of third-dose vaccination in December 2021, it was not possible to determine whether differences we observed between Delta and the BA.1 and BA.2 VOCs were attributable to intrinsic differences between these variants, or waning of immune protection afforded by vaccination. The reported shift in COVID-19 symptoms between Delta and Omicron sub-variants may be driven by intrinsic differences in the biology of the virus itself, leading to modified host responses; mutations in the Spike protein of SARS-CoV-2 VOCs may directly impact on symptom profiles through changes in viral tropism (2, 3, 32, 33), However, detailed data on differences in the host response to different VOC in vaccinated, non-hospitalised adults are currently lacking, but are likely to involve an interplay between localised mucosal innate and early T-cell interferon-mediated systemic responses (2, 34, 35). Further studies to determine the mechanisms by which different and emerging VOCs affect the host response are urgently required, and will be a necessary counterpart to clinical studies in the assessment of future VOCs.…”

“…The reported shift in COVID-19 symptoms between Delta and Omicron sub-variants may be driven by intrinsic differences in the biology of the virus itself, leading to modified host responses; mutations in the Spike protein of SARS-CoV-2 VOCs may directly impact on symptom profiles through changes in viral tropism (2-4, 49, 50). Detailed data on differences in the host response to different VOC in vaccinated, non-hospitalised adults are currently lacking, but are likely to involve an interplay between localised mucosal innate and early T-cell interferon-mediated systemic responses (2, 51, 52).…”

Transcriptionally active nasopharyngeal commensals and opportunistic microbial dynamics define mild symptoms in the COVID 19 vaccination breakthroughs

“…Chandramani et al demonstrated that fully vaccinated individuals from an eastern state of India were less likely to develop severe disease [1]. As much as vaccination reduces COVID 19 hospitalizations, there have been significant number of 'breakthrough' infections worldwide, including India, after double dose vaccination, thus allowing the chance of subsequent transmission [2] [3]. Consequently, it is imperative to understand why a subset of patients acquire infection/s after administration of vaccine doses?…”

Mutational dynamics across VOCs in International travellers and Community transmission underscores importance of Spike-ACE2 interaction

“…Subsequently, many different VOCs emerged from different parts of the world - Beta (South Africa), Gamma (Japan) and Delta (India). Many VOCs caused a fresh round of infections and mortality, putting further strain on public healthcare infrastructure and medical support ( Kanakan et al 2022 ). India also experienced waves of enhanced COVID-19 infections, the first wave between March 2020-Sept 2020 and the second one from March 2021-June 2021 (Kar et al 2021).…”