In a recent study published in the Frontiers in Immunology Journal, a group of researchers examined the immune response and potential cross-protection in hospitalized patients with breakthrough infections caused by the Delta and Omicron variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Study: Immune responses in COVID-19 patients during breakthrough infection with SARS-CoV-2 variants Delta, Omicron-BA.1 and Omicron-BA.5. Image Credit: Naeblys/Shutterstock.com
Background
The coronavirus disease 19 (COVID-19) pandemic has resulted in millions of infections and deaths worldwide. Vaccines have been crucial in reducing the spread of the virus.
Messenger ribonucleic acid (mRNA) vaccines like Comirnaty and Spikevax have been widely administered in Germany, effectively protecting against SARS-CoV-2. However, new variants of concern, such as Omicron, have emerged, posing challenges to vaccine effectiveness.
Omicron is particularly evasive to antibodies generated by vaccines. Despite breakthrough infections among vaccinated people, most remain protected from severe illness. However, the immune response to specific Omicron sub-variants, viz. BA.1 and BA.5, are not well understood.
About the study
The study population involved 52 hospitalized patients with confirmed SARS-CoV-2 breakthrough infections and a control group of 28 individuals without SARS-CoV-2 infection. Among the patients, 25 were infected with the Delta variant, 15 with the Omicron-BA.1 variant, and 12 with the Omicron-BA.5 variant.
Most Delta-infected individuals were double vaccinated, while most Omicron-BA.1 patients were double or triple vaccinated, and all Omicron-BA.5 patients had received a booster dose. The control group had varying levels of vaccination. Patient samples, including blood samples and nasopharyngeal swabs, were collected for analysis.
To characterize the SARS-CoV-2 strains and immune responses, viral ribonucleic acid (RNA) was isolated and sequenced, and phylogenetic analysis was performed. The study also measured immunoglobulin G (IgG) antibodies against the SARS-CoV-2 spike protein and IgM/IgG antibodies against the nucleocapsid protein using enzyme-linked immunosorbent assay (ELISA).
Neutralization assays were conducted to assess the ability of patient sera to neutralize different SARS-CoV-2 variants. Additionally, an Interferon-gamma (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay was performed to evaluate the cell-mediated response to the virus.
Statistical analyses were conducted to assess significant differences between groups using tests such as Kruskal-Wallis, Mann-Whitney U, Wilcoxon signed-rank, and Fisher's exact tests. Correlation coefficients were calculated using Spearman's rank analysis.
Study results
The study conducted sequencing and phylogenetic analysis of the SARS-CoV-2 variants causing infections. Researchers reported that most breakthrough infections occurred in individuals who had received at least one vaccine dose, with varying vaccination levels in the control group.
Whole genome sequencing of clinical isolates revealed that patients were infected with the Delta variant or the Omicron sub-lineages viz. BA.1 and BA.5.
Further, when serum samples were tested for SARS-CoV-2-specific antibodies using ELISA, most samples were positive for subunit 1 (S1)-specific IgG antibodies, indicating a humoral immune response. Antibody levels against the nucleocapsid protein (NCP) were much lower than S1.
There were no significant variations in antibody levels between different breakthrough infection groups based on the vaccine status.
Neutralization assays were performed to evaluate the ability of patient sera to neutralize different SARS-CoV-2 variants. Sera from breakthrough-infected patients showed reduced neutralization capacity against Omicron sub-lineages BA.5 and BA.1 compared to Alpha, Delta, and wild-type variants.
However, patients with Delta breakthrough infections who received two vaccine doses had a significantly enhanced neutralizing antibody response against the Delta variant compared to uninfected controls.
Cellular immunity was assessed using an IFN-γ ELISpot assay. Double-vaccinated Delta-infected patients showed the highest response to NCP stimulation, followed by boosted patients infected with the BA.5 variant. Delta-infected patients responded significantly more to wildtype S protein than BA.1-infected patients. All groups showed a lower response to mutated SARS-CoV-2 variants.
Correlations were observed between neutralizing antibody titers, S1-specific IgG antibody levels, and the cellular immune response. The highest correlation between neutralizing antibody titers against Alpha and wild-type variants was found.
However, the correlation was lower for Delta and Omicron variants. A correlation was also found between S1-specific IgG antibody concentrations and the cellular immune responses against wildtype, but not against SARS-CoV-2 variants.
Discussion
The study highlights several important findings. Firstly, the neutralizing antibody titers against the Omicron sub-variants were significantly reduced compared to other variants, indicating a substantial immune escape of these sub-variants.
This aligns with previous research showing their ability to evade antibodies from vaccinated or infected individuals with other Omicron sub-lineages.
The study demonstrated a strain-specific enhancement of neutralizing immunity in patients with Delta and Omicron-BA.1 breakthrough infections. Delta infections significantly enhanced neutralizing antibody titers against Delta, surpassing the levels observed against the wildtype strain.
Similarly, Omicron-BA.1 breakthrough infections enhanced neutralizing antibody titers against BA.1 and Delta, suggesting cross-reactive immunity between these variants. However, BA.5 breakthrough infections did not result in an immune boost, indicating that BA.5 has a weaker effect on humoral immunity and may increase the risk of reinfections.
The study also assessed cellular immunity using an IFN-γ ELISpot assay. The response to distinctly mutated regions of all SARS-CoV-2 variants was weak, possibly due to the early stage of infection at the time of sample collection.
However, all patient groups exhibited a strong IFN-γ response when stimulated with the spike protein of the Wuhan wildtype, indicating a robust cellular immune response regardless of vaccination status or variant causing breakthrough infection.
Conclusions
The study provides valuable insights into the immune response to breakthrough infections with Delta and Omicron variants. The reduced neutralizing antibody titers against Omicron sub-variants highlight the challenge posed by these highly evasive variants.
The findings of strain-specific immune boosting and the lack of immune enhancement in BA.5 infections contribute to our understanding of vaccine effectiveness and the potential for reinfections with emerging variants.
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