Study investigates whether immune responses to BNT162b2 vaccine differ in subjects with and without prior SARS-CoV-2 infection

The rollout of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was expected to achieve population-level immunity preventing reinfection, and thus an eventual end to the pandemic of coronavirus disease 2019 (COVID-19). However, the emergence of variants that demonstrate resistance to neutralization by antibodies to the ancestral virus or earlier variants threatens the achievement of this goal.

Study: SARS-CoV-2 BNT162b2 vaccine-induced humoral response and reactogenicity in individuals with prior COVID-19 disease. Image Credit: Irina Shatilova/ShutterstockStudy: SARS-CoV-2 BNT162b2 vaccine-induced humoral response and reactogenicity in individuals with prior COVID-19 disease. Image Credit: Irina Shatilova/Shutterstock

A new paper published in the journal JCI Insight reports on the differential levels of immunity achieved in those with and without a history of prior infection with the virus following one and two doses of the earliest vaccines to be approved for emergency use – the messenger ribonucleic acid (mRNA) vaccines from Pfizer and Moderna.


Both these vaccines have shown 90% to 95% efficacy against infection with the virus, and complete effectiveness against severe COVID-10, in late-stage clinical trials, though in real-world settings, reinfections and deaths following double-vaccination have been reported in non-negligible numbers.

However, Israel has reported similarly high levels of protection after country-wide immunization with the Pfizer vaccine. Two doses of these vaccines are recommended for Americans by the public health authorities irrespective of a history of prior infection with the virus. This ignores the fact that trial data did not include infected participants, and the demonstration of long-term immunity in recovered COVID-19 patients, along with low rates of reinfection so far.

Earlier studies have shown that those with prior infection show both rapid and robust antibody and cellular adaptive immune responses after one dose of an mRNA vaccine, peaking at levels above those seen in infection-naïve subjects. As a result, some have suggested that following infection, one dose of these vaccines is adequate for protective immunity, thus saving on vaccines and making more of these vaccines available for the population at greater risk.

Yet, there is little data to provide a definitive description of what happens following the second dose of vaccine at the standard dosing interval of three to four weeks. The current paper examines this response regarding anti-spike antibodies to the receptor-binding domain (RBD) and serum neutralizing activity, measured at two-week intervals for 56 days from the first dose and 35 days from the second day in both infected and infection-naïve subjects.

What did the study show?

The results show that both binding and neutralizing anti-spike antibody activity increased over time in response to the vaccine in naïve and previously infected subjects. However, the trajectory and magnitude differ with a history of prior infection.

The mean age was around 45 years in both groups, most patients being White. Over 90% were symptomatic. The average duration between symptom onset and first vaccine dose was seven months, but almost 60% received the first dose later than this. However, there was no correlation between the peak antibody titer and the duration since symptom onset.

Before vaccination, the antibody titers to the spike RBD or nucleocapsid proteins were raised in over 80% of those with prior infection but not the controls. Neutralizing activity was not significantly raised in the COVID group, however.

Following vaccination, the spike RBD antibody levels varied considerably in both groups between individuals and also between groups. In participants with prior COVID-19 history, the rise was more rapid, the peak level lower, and the decline slower than in the control group.

The titer at day 14 from the first dose was higher than before vaccination but remained stable at this level thereafter. The peak occurred at day 28 post-first dose in over 60%, and at day 14 in over a third. None of them showed a peak at day 56.

Conversely, in the control group, there was no significant rise by day 14, while thereafter levels rose to peak by day 28 in 60%, and by day 42 in 37%, of subjects. The peak values were higher in the control group.

Spike RBD antibodies declined markedly in the control group, but this was not reflected in the COVID-19 group. Meanwhile, the nucleocapsid antibody titer was undetectable in controls and waned over time in the COVID group.

Neutralizing activity rose 17-fold in the COVID group by day 14 from the first dose, compared to pre-vaccination levels. The difference from the titers in the control group was 25-fold. Thereafter this remained unchanged, while in the control group, it rose rapidly. By day 42, both groups showed comparable neutralizing activity.

Systemic symptoms like fever, body ache, tiredness, and headache were more common. They lasted longer after either dose of vaccine in the COVID group, but local reactions were similar in both groups. Neither group reported any need for medical care.

What are the implications?

This study showed that antibody responses to the spike RBD and neutralizing activity were higher in the COVID group than in the infection-naïve group, which lasted longer. However, the response was flatter compared to the naïve group. Most of the group showed peak anti-RBD antibody levels at day 28 from the first injection without a further rise in titer, while neutralizing activity also followed the same trend.

The spike RBD response to the first dose is thought to be an anamnestic response triggered by long-memory B and T cells, which have been shown to circulate in the blood, along with bone marrow plasma cells, T follicular helper cells, and both CD4 and CD8 T helper Th1 cells for up to 11 months from infection. This also explains why the second dose failed to create any heightened response.

Nucleocapsid antibodies were found only in the COVID group but did not rise thereafter in this group. The presence of these antibodies ruled out the protective effect of COVID-19 during the vaccination period in either group.

Systemic symptoms occurred more frequently and intensely in the COVID group after vaccination, especially after the first dose.

Further research is required to elucidate the long-term antibody titers, as the study period was limited to 56 days. Secondly, most of the COVID group was symptomatic, and several had a moderate-to-severe disease, which could drive the response higher. Finally, neutralizing activity was assessed only for the spike protein of the ancestral variant but not for the recently emerging variants.

The high levels of spike RBD antibodies seen early in the post-first dose course of immune activation indicate that this existed against a broad range of SARS-CoV-2 variants, even before the second dose.

These results agree with earlier studies showing better immune responses to the mRNA vaccines in those with a history of SARS-CoV-2 infection than the infection-naïve subjects. Neutralizing activity against other variants of the virus also increases significantly after the first vaccine dose.

In the current study, the onset, peak, and initial waning of the anti-spike RBD antibody titers were followed and defined more precisely, for the first time, in those with and without a history of COVID-19.

Our data on minimal responses in the two groups can be used to assess the appropriateness of the anti-Spike RBD antibody response to BNT162b2 in potentially immunocompromised individuals... may facilitate medical decision making with regard to the vaccine response in individual patients.”

Another implication is that the response to the second dose of the vaccine is almost undetectable in those with a history of prior infection with the virus, indicating that a single dose may be adequate.

The prior bout of COVID-19 may have provided sufficient immune stimulation such that the first dose of vaccine elicited a maximal or near maximal response.”

This could direct many vaccine shots to people who need them more. In contrast, the lowered immunity to the newer variants has been shown to be boosted by additional doses of the vaccine. This requires further clinical trials to make the final decisions on the vaccine regimen for those with and without a history of prior infection.

Journal reference:
Dr. Liji Thomas

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.


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  1. Hannah Cole Hannah Cole People says:

    RNA In Situ Hybridization is a widely-applicable histology technique that utilizes a nucleic-acid based probe to localize to RNA sequences of interest, and allows for visualization of mRNA expression in cells or tissues. This technique can provide valuable special and temporal information regarding gene expression in situ, such as whether expression at the mRNA level is limited to a specific anatomic structure or cell type.

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