Could an mRNA vaccine second dose reduce cellular immunity in previously infected individuals?

As the pandemic of coronavirus disease 2019 (COVID-19) continues to spread the world over, the focus of scientific research has been on the development of effective and safe antivirals and vaccines against the causative agent: the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pathogen.

A new study, which was released on the bioRxiv* preprint server, shows the differential effect that a standard vaccine protocol may have on individuals, based on their history of prior infection with the virus.

The mRNA vaccine

The need to relax non-pharmaceutical interventions (NPIs) led to the accelerated release of several vaccines, based on different platforms. These include the BNT162b2 mRNA (messenger ribonucleic acid) vaccine developed by Pfizer/BioNTech, which received emergency use authorization by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in December 2020.

This vaccine contains a transcribed RNA sequence encoding the SARS-CoV-2 spike protein, which is one of its dominant immunogens.  The vaccination protocol for this vaccine includes two doses separated by a 21-day interval. The clinical trials of this vaccine showed a high efficacy against symptomatic infection, about 95%, in naïve individuals.

The immunity elicited by this vaccine includes both antibody-mediated and cellular immunity. The question to be faced is whether it acts the same way in previously infected individuals.

Discrepancies in immune responses with pre-existing immune status

The first dose has been observed to result in a strong spike-directed antibody and T cell response in such subjects. However, there is a significant body of scientists who opine that the second dose of this vaccine may not be useful in this group.

In support of this view, the second dose has been shown to have a deleterious effect on the overall antibody response specific to the spike antigen, in this class of vaccinated individuals.

Study aims

The current study aims to answer the question of how the second dose affects the T cell response to the spike, in both uninfected and exposed individuals. If T cell immunity is impaired, the resulting activation of adaptive humoral responses is likely to be impaired as well, lowering the degree of protection afforded by the vaccine in this group.

Despite the importance of this issue, the multiple aspects of monitoring the T cell response elicited by the viral spike, in terms of quantitative and qualitative assessments, has hindered a full understanding of the cellular immune response to vaccination.

Use of proxy for T cell responses

The current study demonstrates that both CD4+ and CD8+ T cell responses to SARS-CoV-2, which have a helper and cytotoxic functions, respectively, can be accurately measured in those with a history of the infection and in vaccine recipients. This was accomplished by direct measurement of interferon (IFN)-γ, as obtained from samples of whole blood stimulated by pooled viral peptides.

Such an approach was used to measure changes in the T cell population before and after (10 and 20 days after) the first and second doses of the vaccine. The vaccine recipients included 23 individuals who had a history of documented SARS-CoV-2 infection, and the same number of naïve individuals.

First dose effects

Before the first dose of the vaccine, the IFN- γ response to the pool of spike peptides, in whole blood, was higher for those who had recovered from this infection relative to the naïve group, at 47 pg/mL vs. 1 pg/mL, respectively.

Similarly, the pooled peptides enhanced IFN- γ secretion in spike-specific CD4+ effector T cells in the recovered group only, indicating that their blood contained memory CD4+ cells specifically reactive to the virus. This study thus showed the release of IFN-γ in whole blood to be an accurate proxy for the T cell response to spike challenge.

At 10 days after the first dose, the IFN- γ response was five-fold higher in the recovered group than in the naïve group, at a median of 520 pg/mL vs. 110 pg/mL, respectively.

At 20 days after the first dose, T cell immunity remained high in the recovered group. However, the IFN-γ response in the naïve group waned rapidly, to about a tenth of that in the first group.

This shows that, as expected, “individuals with pre-existing immunity exert a more potent and sustained T cell response to SARS-CoV-2 spike after the first dose of the vaccine.”

Second dose effects

When naïve individuals were tested at 10 days from the second dose, the IFN-γ levels went up to a median of 160 pg/mL, compared to the 1 pg/mL at baseline. This was mirrored in the spike-specific immunoglobulin G (IgG) levels in this group.

Thus, naïve individuals showed a marked increase in both IgG levels after the second dose, implying adequate protection after two doses of vaccine in this group.

In the case of recovered individuals, IFN-γ levels dropped on day 10, to a median of 210 pg/mL compared to the baseline of 47 pg/mL. This indicates a counterproductive effect of the second dose of vaccine in this group, implying that a change may be required to the standard regimen.

At day 20, however, both naïve and recovered individuals showed comparable IFN-γ levels, at 88 pg/mL and 136 pg/mL, respectively.

What are the implications?

One dose of the BNT162b2 mRNA COVID-19 vaccine induces robust cellular and humoral immune responses in both naïve and recovered individuals. In the first group, the T cell response wanes rapidly, but increases again after the second dose, along with spike-directed IgG production.

In the group of recovered individuals, the second dose actually reduces the specific T cell response elicited by the first dose. This could lead to the conclusion that the second dose should not be given, at least until further knowledge is gained on this aspect of vaccination, to maintain the high T cell response.

These startling findings need to be explained. Perhaps, the researchers say, “the effector memory CD4+ T cells expanded by first vaccine dose in COVID-19 recovered individuals may be prone to activation-induced cell death (AICD) after the second vaccination dose.”

It is also possible that the observed effect is due to functional exhaustion of the spike-targeting T cells but without a reduction in the actual number of long-term effector memory T cells. Phenotypic studies of the T cell subsets in both these groups are required to understand which of these explanations is correct.

However, in the face of current vaccine shortages, the use of specific tests to detect cellular immunity against SARS-CoV-2 may allow strategies to be designed that prioritize individuals without detectable pre-existing immunity against the virus for the second dose of the vaccine.

This should be accompanied by providing vaccination certificates to the recovered individuals after a single vaccine dose.

*Important Notice

bioRxiv 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.

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.