Health

Past SARS-CoV-2 infection enhances mRNA vaccine-induced neutralization of variants of concern

Researchers in the United States have conducted a study suggesting that individuals previously infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exhibit better neutralizing activity against variants of concern following vaccination against coronavirus disease 2019 (COVID-19) than previously uninfected vaccinees.

“Plasma from previously infected vaccinated individuals displayed overall better neutralization capacity when compared to plasma from uninfected individuals that also received two vaccine doses, pointing to vaccine boosters as a relevant future strategy to alleviate the impact of emerging variants on antibody neutralizing activity,” writes the team from Yale University School of Medicine and Yale School of Public Health in New Haven, Connecticut.

The team found that while previously infected vaccinees initially sustained higher antibody titers against an ancestral SARS-CoV-2 strain (Wuhan-Hu-1) than vaccinees without previous infection, the latter group reached comparable levels of neutralizing antibodies after a second vaccine dose.

However, Akiko Iwasaki and colleagues also found that previously infected individuals exhibited more significant neutralization activity against SARS-CoV-2 variants of concern than those without previous infection, even after both groups had received two vaccine doses.

A pre-print version of the research paper is available on the medRxiv* server, while the article undergoes peer review.

The concerns surrounding SARS-CoV-2 variants

The messenger RNA (mRNA-based) COVID-19 vaccines developed by Pfizer-BioNTech (BNT162b2) and Moderna (mRNA-1273) encode a full-length ectodomain of the SARS-CoV-2 spike protein derived from the ancestral strain that was isolated in Wuhan, China.

The spike protein mediates the initial stage of the infection process and is the primary target of neutralizing antibodies following natural infection or vaccination.

However, emerging SARS-CoV-2 variants containing mutations in the spike gene have been associated with increased transmissibility, as well as resistance to neutralization by convalescent plasma and sera from vaccinees.

What did the researchers do?

The team assembled a cohort of previously infected (recovered) and uninfected (naïve) individuals who had received either the Pfizer-BioNTech or Moderna vaccine. The researchers characterized virus-specific immunologic profiles longitudinally across five time points, covering a period of 98 days following the first vaccine dose.

The study included a total of 198 samples collected from 40 healthcare workers from the Yale-New Haven Hospital who were enrolled between November 2020 and January 2021.

What did they find?

The researchers found that SARS-CoV-2-specific immunoglobulin G (IgG levels) were significantly higher in the previously infected vaccinees than in the uninfected vaccinees.

The team longitudinally assessed the plasma neutralization activity against an authentic SARS-CoV-2 strain (USA-WA1/2020; lineage A) with a similar spike gene amino acid sequence to the Wuhan-Hu-1 isolate.

This revealed that previously infected individuals sustained higher antibody titers than uninfected individuals did post-vaccination.

However, the two groups exhibited similar neutralization titers at the peak of response (seven days after the second vaccine dose).

“Our data indicate that despite faster and more exuberant antibody responses to viral proteins by previously infected vaccinated than uninfected vaccinated individuals, vaccination led to similar overall levels of neutralizing antibodies after the second dose,” says Iwasaki and colleagues.

Examining neutralization titers against variants

Next, the team determined the neutralization titers generated against a panel of 16 isolates of distinct locally circulating SARS-CoV-2 variants.

The researchers found that plasma from previously infected vaccinated individuals generally exhibited a better neutralization capacity against the panel, compared with plasma from previously uninfected individuals.

Gating strategies. Gating strategies are shown for the key cell populations described in Figure 2 and Extended Data Figure 2. a, Leukocyte gating strategy to identify lymphocytes. T cell surface staining gating strategy to identify CD4 and CD8 T cells, TCR-activated T cells and follicular T cells. b, B cell surface staining gating strategy to identify B cells subsets.

Gating strategies. Gating strategies are shown for the key cell populations described in Figure 2 and Extended Data Figure 2. a, Leukocyte gating strategy to identify lymphocytes. T cell surface staining gating strategy to identify CD4 and CD8 T cells, TCR-activated T cells and follicular T cells. b, B cell surface staining gating strategy to identify B cells subsets.

However, the study revealed a range of reductions in neutralization capacity that was associated with specific spike gene mutations.

For example, compared with lineage A, the B.1.351 (beta) variant of concern (VOC) that contains mutations E484K and N501Y decreased neutralization titers by 13.2-fold and by 3.7-fold in previously uninfected versus infected vaccinees.

For the B.1.617.2 (delta) VOC that contains mutation L452R, the corresponding decreases were 6.9-fold and 1.5-fold and for the B.1.1.7 (alpha) VOC that contains N501Y, the corresponding decreases were 3.4- and 0.8-fold.

Booster shots may help overcome the reduced neutralization observed for variants

Iwasaki and colleagues say the study suggests that plasma neutralization activity against SARS-CoV-2 variants is improved in vaccinated individuals previously infected with the virus.

They also say the findings show that that virus genotype plays an important role in vaccine-induced neutralization.

“L452R likely has the largest individual impact, but the added effects of E484K and N501Y make viruses with this combination perhaps the most concerning for vaccines,” writes the researchers.


“These results suggest that future vaccine boosters (third dose) may help to overcome the reduction in neutralization capacity observed for the variants, in particular those of the genotypes with the L452R (e.g., B.1.617.2) or the E484K and N501Y combination (e.g., P.1 and B.1.351),” advises the team.

*Important Notice

medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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