In a recent study published in Nature Communications, researchers examine the effect of infection and coronavirus disease 2019 (COVID-19) vaccination in healthy individuals with diverse imprinted immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: Previous immunity shapes immune responses to SARS-CoV-2 booster vaccination and Omicron breakthrough infection risk. Image Credit: Kateryna Kon / Shutterstock.com

Background

The continual emergence of novel SARS-CoV-2 variants, combined with widespread vaccination rates, directly contributes to the present transmission dynamics of SARS-CoV-2. The truth is, the frequency of breakthrough infections (BTIs) in vaccinated individuals, including reinfections, is progressively increasing, particularly after the emergence of the SARS-CoV-2 Omicron variant and its sublineages. 

Several aspects, including age, gender, comorbidities, and prior infection history, influence humoral and cellular immune responses after vaccination. Consequently, post-vaccination immunity is extremely heterogeneous across individuals. Up to now, it stays unclear why some individuals are at an increased risk of primary infections and reinfections, particularly from the Omicron and its subvariants, even after getting vaccinated against COVID-19.

Several studies have described the concept of immune imprinting, which is the shortcoming of the immune system to mount an efficient response to infection by a brand new variant or vaccines resembling the unique immunogen for the influenza virus, human immunodeficiency virus (HIV), and SARS-CoV-2. Nevertheless, whether the systemic immunoglobulin A (IgA) response is related to protection against SARS-CoV-2 BTIs stays unknown.

In regards to the study

In the present prospective observational study, researchers recruited healthcare professionals from Rigshospitalet and Herlev-Gentofte University hospitals in Denmark. All study participants received a two-dose primary series and booster dose of the Pfizer-BioNTech BNT162b2 COVID-19 vaccine.

Study participants provided venous blood samples at baseline, 21 days, two, six, and 12 months after receiving the primary vaccine dose. An enzyme-linked immunosorbent (ELISA)-based assay was used to quantify IgG and IgA levels within the plasma. Moreover, the Elecsys® Anti-SARS-CoV-2 assay was used to quantify total antibodies against the SARS-CoV-2 nucleocapsid (N) protein, which reflects previous SARS-CoV-2 infection.

An ELISA-based pseudo-neutralizing assay was used to estimate the inhibitory potential of neutralizing antibodies (nAbs) against the SARS-CoV-2 receptor-binding domain (RBD). Interferon-gamma (IFN-γ) levels released from stimulated T-cells in patient whole blood samples were also measured.

Study findings

The third vaccine dose, often known as a booster dose, resulted in a significantly increased IgG response to the SARS-CoV-2 RBD. This response was directly related to the age, sex, and infection status of the person.

Comparatively, age and gender didn’t influence nAbs levels following booster vaccination. This is probably going because antibody affinity maturation occurs after the booster dose and is more pronounced in individuals with hybrid immunity.

The reinfection rate was higher amongst individuals previously infected before Omicron at 37.5%, whereas 48.4% of infection-naive individuals contracted Omicron infection after booster vaccination. Amongst Omicron-infected individuals, those sampled after 12 months exhibited significantly reduced levels of IgG/IgA and nAbs following primary vaccination as in comparison with infection-naive individuals.

Is vaccination or infection more protective?

It stays unclear whether immune imprinting in unvaccinated individuals modulates immunity at vaccine priming, thus necessitating granular data to elucidate in-depth B memory cell responses. Nevertheless, the study findings exhibit that individuals experiencing reinfections had a weaker humoral response, characterised by a lower peak and marked waning after the vaccine priming.

Previous studies have documented discrepancies regarding the association between IgG and mucosal IgA. In the present study, the neutralizing activity of IgG was likely enhanced by vaccination; nevertheless, this antibody response was more distinguished in previously infected individuals. The protective role of serum IgA, as in comparison with IgG, against SARS-CoV-2 infection appears to be short-term and modest. 

Since cellular immunity stays unaltered after vaccination, it is probably going answerable for stopping severe COVID-19 outcomes despite being ineffective against SARS-CoV-2 transmission and BTIs. Accordingly, IFN-γ levels of vaccinated individuals experiencing Omicron reinfection and vaccinated individuals experiencing a primary Omicron infection were comparable. Indeed, vaccination triggered a sturdy cellular response that was boosted further after the primary viral exposure.

Although IgA antibodies are the first defense mediator on mucosal surfaces, the researchers of the present study couldn’t conclusively determine the origin of IgA in circulation and whether infected and naive individuals had comparable IgA portfolios.

Conclusions

Pre-existing immunity of a person against SARS-CoV-2 significantly impacts their humoral and cellular responses after booster vaccination, as demonstrated by a sturdy IgA response observed in previously infected individuals following booster vaccination. Nevertheless, in the present study, primary Omicron infection and subsequent Omicron reinfection significantly reduced these responses.

Using different vaccine boosters, combined with frequent mutations in novel SARS-CoV-2 variants, has increased the complexity of immune responses to SARS-CoV-2, which, in turn, complicates future COVID-19 vaccine strategies. Thus, continued research on immune responses to SARS-CoV-2 is crucial for the event of latest and effective vaccines able to eliciting effective IgA responses.