Covid-19 vaccine: Time to test Covishield-Covaxin mix for immune response against D variant

The puzzling question that would arise in most minds is as to how a vaccine that produces less antibodies is more protective against breakthrough infection.

Sibling rivalry between Covishield and Covaxin, which flared briefly at the time of their emergency approvals in January 2021, got sparked again recently when Indian researchers shared pre-publication data on vaccine-induced immune response with the media. The study was conducted on 515 healthcare workers (all doctors) in 22 cities in 13 states, during January to May 2021, following their vaccination.

Vast majority of the participants received Covishield, though the smaller number receiving Covaxin is variably reported as 90 and 93 in the report. Participants were tested for antibodies against the spike protein of the SARS-CoV-2 virus, after the first dose and the second dose of each vaccine. Breakthrough Covid-19 infections were also recorded. After two doses of both vaccines, 95% showed seropositivity for the tested antibodies.

The researchers report that antibodies against the spike protein were higher in those who received Covishield than among those who received Covaxin. They stated that the former group had 10 times higher antibody levels than the latter, after the first dose. After the second dose, the difference was six-fold. The authors state that among those who ‘never had Covid’, 97.8% of those who received both doses of Covishield were seropositive for antibodies, compared to 79.3% of two-dose Covaxin recipients.

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Breakthrough infections were defined as “testing positive for the virus two weeks or more after the second dose”. Here, Covaxin recipients were reported to fare better, with 2.2% of that group testing positive, compared to 5.5% in the Covishield group. The small sample size of the Covaxin group yields wide 95% confidence intervals (uncertainty bands) around the point estimates derived from that group. Even if point estimates appear different, overlapping confidence intervals will not permit conclusions of real differences between the groups.

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Media reports of this non-peer reviewed report drew a critical comment from a scientist associated with Covaxin, who pointed out that prior Covid was ruled out only by offered history and not by lab testing for virus or baseline antibodies. The implication was that untested individuals may have had asymptomatic Covid infection resulting in heightened immunogenicity following vaccination. If such persons were more among the numerically much larger Covishield group, higher antibody levels would be a result of the combined effect of the infection and vaccination and not the latter alone.

If only the reported point estimates are relied upon, without concern about the wide uncertainty band, explanations have to be sought for the contrasting effects of the two vaccines on potency and protection. The puzzling question that would arise in most minds is as to how a vaccine that produces less antibodies is more protective against breakthrough infection.

Theoretical grounds do exist, to explain. Covishield carries the code for production of the spike protein in the recipient’s body, to trigger strong antibodies against that antigen. Other parts of the SARS-CoV-2 virus are not introduced to the body. Covaxin, on the other hand, is an inactivated virus which offers the body’s immune system a larger platter of antigens to react against. As the body’s immune response is spread wider, antibody production against the spike protein antigen may be less intense. It is the water jet effect versus the shower effect.

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For the same reason, of a widespread immune response, Covaxin may offer a better protection against breakthrough infection by variants that have developed mutations against the spike-protein antibody. The umbrella of protection is larger, as other viral antigens too can be targeted by the broad-band immunity elicited by the inactivated whole virion. Variants may evade spike-protein-specific antibodies, which may be more abundant but less effective after Covishield. Real world evidence, provided recently by Public Health England, shows lowered efficacy of spike-protein-specific vaccines against the A and D variants, both of which were circulating in India during the study period. From January to March, the A variant was quite prominent in several parts of India.

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The D variant shared the stage with the A variant in March, but has since cornered the limelight. For us to consider whether the seemingly better protection offered by Covaxin against breakthrough infections calls for better studies, with larger sample sizes and genomic testing added where possible. Baseline antibody levels would have helped. However, what matters in the real world is the answer to the question “how well did the vaccine protect against breakthrough infection and severe Covid-19?”. Without adequate data to answer that question, any discussion of comparative efficacy will remain frustratingly futile. History of medicine is replete with studies which produced impressive results on surrogate intermediate variables, but failed to impact meaningful clinical outcomes in trials.

Correlates of vaccine protection are not limited to antibodies alone. T-cells play a very important role too, both in early response and storing memory of the antigens they encounter. After the SARS outbreak (2001-3), none of the survivors has antibodies after six years, while memory T-cells were detected in all after 17 years. While antibodies combat viruses in the blood, T-cells provide protection against intracellular viral infections like Covid-19.

Mixing of vaccines for the two shots is also attracting scientific interest. A recent German study, in 26 young persons, observed that a mix of AstraZeneca and Pfizer shots produced 3.9 times higher levels of neutralising antibodies against Alpha and Beta variants. Perhaps it is time for our scientists to test whether a mix of Covishield and Covaxin will enhance both potency and protection against the D variant. The siblings can then battle the virus together and not each other.

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The author, a cardiologist and epidemiologist, is president, Public Health Foundation of India
Views are personal

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