The coronavirus disease 2019 (COVID-19) pandemic led to a spurt of activity to develop safe and effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first to be developed were the two messenger ribonucleic acid (mRNA) vaccines from Moderna and Pfizer, with 94% or higher efficacy reported from phase 3 clinical trials.
Study: Ad26.COV2.S or BNT162b2 Boosting of BNT162b2 Vaccinated Individuals. Image Credit: Tobias Arhelger/Shutterstock
However, the immunity produced by these vaccines, particularly the latter (BNT162b2), has been reported to wane after about six months, allowing breakthrough infections or reinfections to occur. To counter this, an additional third booster dose has been rolled out in several countries, notably Israel.
*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.
A new preprint discusses the immune boost resulting from homologous or heterologous booster doses in individuals fully vaccinated with two doses of the Pfizer vaccine.
Background
Earlier studies showed that while a full vaccination course with either of the two mRNA vaccines elicited a robust protective response against SARS-CoV-2, the immunity waned over time, leading to breakthrough infections. This was exacerbated by the emergence of new virus variants, some of which had mutations that affected the host immune response and/or evaded antibody recognition. Such was the case with the Beta and Delta variants, labeled variants of concern (VOCs).
As the Delta virus rose to dominance the world over, the number of breakthrough infections rose correspondingly. In response, a third dose of the same vaccine used in the primary series was given to those vaccinated six or more months before. This was reported, in earlier studies, to be associated with higher antibody titers even than in the first two months following the second dose of the vaccine and with greater protection against the ancestral virus and its VOCs.
The current study, which is available as a preprint on the medRxiv* server, compares both antibody-mediated and cellular immune responses in individuals who had received two doses of the Pfizer vaccine and then received an additional dose of either the same or the Johnson & Johnson Ad26.COV2.S adenovirus vector vaccine, at six or more months from the second dose.
What did the study show?
Neutralizing antibodies
The researchers found that neutralizing antibodies appeared to be present at low levels in the serum at six months from the second BNT162b2 dose. They were capable of neutralizing pseudoviruses bearing the SARS-CoV-2 spike. However, the steep decline agreed with earlier studies showing the waning of humoral immunity in these individuals at this time point.
When boosted with Ad26.COV2.S, the median neutralizing antibody titer increased sharply, against the wildtype, Beta, and Delta variants of the virus, at just two weeks from the third dose. The titer of antibodies effective against the wildtype increased the most, to almost 1,500, while the lowest increase was approximately 900 with antibodies to the Beta variants. At four weeks, the titers increased to double or 2.5-fold the levels at two weeks, but with the highest titers of >3,500 against the wildtype virus, vs. greater than 2,000 against the other two variants.
With a BNT162b2 third-dose booster, median neutralizing antibody titers doubled only for those against the wildtype virus at week 2, to >7,500, 3,000, and 2,000, respectively for wildtype, Delta, and Beta variants. At week four, titers were lower, at >5,500, 2,000, and >1,500, respectively.
At week four post-booster, wildtype variant antibodies at this point remained above the levels achieved after the second dose. Conversely, the titers of antibodies to the Beta and Delta variants declined to levels comparable to those at week four from the second dose.
Binding antibodies
As for antibodies to the receptor-binding domain (RBD), an Ad26.COV2.S boost produced very high median titers against the wildtype, Delta, and Beta variants. The increase was of the order of several-fold in all cases, reaching levels of above 11,000, 10,000, and 5,000 at two weeks, and even higher at week four, at over 16,000, 13,000, and 10,000.
With the BNT162b2 boosting, the median anti-RBD titers increased to above 30,000, 26,000, and 14,000 at week 2 for wildtype, Delta, and Beta variants, but these declined to half by week four.
The results show that following a BNT162b2 booster dose, the highest levels are at two weeks, while Ad26.COV2.S boosting leads to peak antibody levels at week four or later. Significantly, at this point, the neutralizing and binding antibody titers against all three variants are at roughly the same levels in both cases.
Cellular responses
The median interferon-gamma (IFN-γ)-producing antiviral spike-specific CD8+ T cell responses to the WA1/2020, Delta, and Beta variants increased following boosting by Ad26.COV2.S, with frequencies of 0.07-0.08%. With a BNT162b2 booster, the corresponding increases were to approximately 0.03% for the wildtype and Delta variants and 0.02% against the Beta variant.
For spike-specific IFN-γ CD4+ T cells, responses against the WA1/2020, delta, and beta variants were boosted by Ad26.COV2.S to approximately 0.1%, while with BNT162b2, the median frequencies were 0.05% against the wildtype vs. 0.04% against the two later variants.
Memory B cell frequencies specific to the RBD increased to a median of 0.4%, approximately, with both vaccines showing predominantly an activated memory cell phenotype at week 2, whichever vaccine was used.
What are the implications?
The data show that heterologous boosting with Ad26.COV2.S or homologous boosting, in individuals who had a primary series of BNT162b2 vaccination at least six months before elicits almost the same final binding and neutralizing antibody titers by week four after the boost to ancestral and newer variants. However, the trajectories of change were different with the two vaccines, showing a steady rise with the former, but a peak followed by the fall from week 2 to week 4 with the latter.
With cellular immunity, the CD8+ T cell frequencies with heterologous Ad26.COV2.S boosting was almost double that achieved with a BNT162b2 booster. Further research will tell how long these cellular responses offer protection against infection. The ability to use heterologous boosters to achieve different types of immune phenotypes is a unique advantage of this approach over the use of homologous boosters.
*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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