Moderate to severe SARS-CoV-2 infection primes vaccine-induced immunity more effectively than asymptomatic or mild infection

As of August 2022, SARS-CoV-2 has caused over 600 million confirmed infections and 6 million deaths globally. While many infections are mild or asymptomatic, the disease severity varies widely. COVID-19 vaccines reduce transmission and severity, but the durability and breadth of protection are unclear, especially against emerging variants. The SARS-CoV-2 spike (S) protein facilitates viral entry, and most vaccines target this protein to induce neutralizing antibodies (Ab) against the receptor-binding domain (RBD) of S1, preventing viral binding to ACE-2. However, non-neutralizing Ab functions and cellular immunity are less sensitive to variant changes and appear crucial for protecting against severe illness. Studies have shown that previous infection primes the immune system for a stronger vaccine response, creating hybrid immunity. This study aimed to determine whether infection severity influences the strength of subsequent vaccine-induced immunity.

The literature review discusses the impact of SARS-CoV-2 infection severity on subsequent immune responses to vaccination. It highlights the role of neutralizing and non-neutralizing antibodies, along with cellular immunity in protection against COVID-19. The authors note that while neutralizing antibodies are susceptible to variant changes, cellular immunity and Fc receptor-dependent non-neutralizing antibody functions are more robust and provide protection against severe disease. Prior research has indicated that individuals with previous SARS-CoV-2 infection have a stronger response to vaccination. This study builds upon this by investigating whether the degree of immune system priming varies with the severity of the initial infection. The authors cite several studies demonstrating that previous infection leads to a stronger immune response to vaccination and that hybrid immunity (infection plus vaccination) provides superior protection than either alone.

Thirty-five individuals with confirmed SARS-CoV-2 infection who received two doses of a COVID-19 mRNA vaccine (either Pfizer-BioNTech or Moderna) were recruited. Participants self-reported their symptom severity, categorized as asymptomatic/mild or moderate/severe. Blood samples were collected before vaccination and after the first and second doses. Humoral immunity was assessed using ELISA to measure IgG antibodies against the full-length S protein and its RBD. Cellular immunity was assessed by ELISpot for IFN-γ-producing T cells and intracellular flow cytometry to analyze cytokine production by CD4+ and CD8+ T cells. Antibody-dependent cell-mediated cytotoxicity (ADCC) was also measured. A control group of 30 COVID-19-naïve individuals who received the same vaccines were also included for comparison. Statistical analyses included Friedman’s test, Dunn’s multiple comparisons test, Mann–Whitney U-test, and Student’s t-test.

Both asymptomatic/mild and moderate/severe groups showed robust increases in humoral and cellular immunity after the first vaccine dose. However, the second dose led to only marginal and short-lived increases in both groups. Importantly, the moderate/severe group consistently displayed significantly stronger humoral and cellular responses compared to the asymptomatic/mild group, both post-infection and after vaccination. This difference persisted even after the second dose. Specifically, the moderate/severe group had higher levels of anti-RBD and anti-FLS IgG antibodies, greater neutralizing antibody titers, and more robust polyfunctional CD8+ T cell responses (producing IFN-γ, TNF-α, and IL-2). The magnitude of T-cell responses to SARS-CoV-2 S peptides was significantly higher in the moderate/severe group compared to the asymptomatic/mild group at all time points. In vitro stimulation of PBMC showed that primary vaccination significantly boosted the frequency of S-specific CD8+ T cells in the moderate/severe group.

The findings indicate that the severity of initial SARS-CoV-2 infection significantly influences the strength and quality of subsequent vaccine-induced immunity. Individuals with moderate to severe COVID-19 experience a more robust priming effect, resulting in stronger and more durable immune responses after vaccination. The stronger CD8+ T cell response in the moderate/severe group suggests a potential long-term immunological advantage. The study highlights the importance of considering individual infection history when designing vaccination strategies. The plateauing of responses after the second dose emphasizes the need for optimized vaccine schedules and potentially different approaches for individuals with varying infection histories. The variation in neutralization capacity relative to antibody levels suggests that both quantity and quality of antibodies contribute to protection.

This study demonstrates that the severity of initial SARS-CoV-2 infection significantly impacts the effectiveness of subsequent vaccination. While both mild and severe infection groups respond robustly to the first vaccine dose, the moderate to severe group maintains superior and more durable immunity. These findings highlight the importance of individual risk stratification in COVID-19 vaccine administration and the need for further research to optimize vaccine strategies based on prior infection history.

The study is limited by its relatively small sample size and the reliance on self-reported symptom severity. The cross-sectional nature of the study means we cannot definitively establish the long-term durability of these immune responses, while the use of self-reported symptoms could lead to some bias in the categorization of infection severity. Additionally, the study focused primarily on ancestral strains, and the findings may not fully generalize to emerging variants.