The idea of heterologous boosting or mixing of vaccines first appeared in Europe, when the AstraZeneca vaccine caused blood clotting in a few people. As a result, many countries recommended a second dose with a different platform (technology) for the young people.
Worldwide, various studies are in progress to ascertain whether a combination of two different vaccines is better than two doses of the same vaccine. In this regard, a research was taken up in June 2021, where a shot of Pfizer’s vaccine was given after an AstraZeneca shot in which it was found that such a mix-and-match approach produced more antibodies than two doses of AstraZeneca. Countries like the UK, Canada, Italy, and the UAE are among those that have allowed mix-and-match inoculation.
As for India, a study by Indian Council of Medical Research (ICMR) has recently come out which also states that mixing of covishield and Covaxin has been found to be safe, but the study has not yet been peer-reviewed.
Viability and Safety of Combination Vaccines
Studies conducted before the emergence of COVID-19 have also shown stronger and broader immune responses with mixing of vaccines of different types. This is perhaps because the shots boost slightly different parts of the immune system or make it identify different parts of an invading pathogen. In the past also, vaccines have been mixed to fight diseases like Ebola and combinations of rotavirus vaccines have been used and tested in India.
Moreover, mixing and matching also “offers much-needed flexibility when vaccine supplies are uneven or limited,” according to the New York Times. As per leading vaccine scientist, Dr Gagandeep Kang, various studies have shown that combinations are not inferior to two doses of the same vaccine. He said, “Theoretically, we can provide some explanation, but there is no data to state whether it is equally immunogenic or in some cases more immunogenic to use a combination of vaccine doses vis-a-vis others.”
Other important basis for mixing vaccines relates to difference in the ability of vaccine platform to induce antibody and T cell (a type of white blood cell and an important part of immune system) response. According to experts, if one platform produces a predominantly antibody response, it can be followed by a platform that generates predominantly a T cell response (e.g., vector and DNA vaccines). This strategy is usually used with a vector-based platform as the first shot followed by a subunit platform. Vector-based vaccines do not contain antigens; they use the body’s own cells to produce them. DNA vaccines use a gene (engineered DNA) from a virus or bacteria to induce the immune system response in the host.
According to Dr Sanjay Pujari, infectious diseases specialist and expert member with the national Covid 19 task force, such heterologous strategies are being studied in HIV, malaria, flavivirus (e.g., dengue), HPV, Ebola, and influenza and are in early-stage trials.
He also opines that for Covid-19, heterologous strategies may be able to induce combined antibody and cell-mediated immune response and result in stronger, broader, and long-lasting immunity. The potential advantages of such a strategy can lead to flexibility in using vaccines based on fluctuation in supplies, a possible robust immune response, and finally efficacy against variants.
However, the preliminary data from Oxford’s Com-COV study indicates that mixing and matching vaccines may result in developing mild and moderate side effects, including fever, fatigue, and headache, most of which will subside within 48 hours. The study suggests that a mismatched regimen “might have some short-term disadvantages”. Possibly, the side effects may be due to a strong immune response. So, the recourse to combination strategy is considered more or less as a viable option.
Need for Caution
Despite positive outcomes of studies on combination vaccines, experts advise to follow a restrained approach on the matter. According to the World Health Organization, the data currently available on the immunogenicity or efficacy of a mix-and-match regimen is not sufficient. The WHO said, “WHO is of the view that the mix-and-match regimens are likely to work. However, we really need to analyse the evidence in each of these vaccine combinations before any other recommendations can be made”.
According to Dr Pujari, “The published evidence for efficacy and safety of heterologous vaccine strategies is limited to 2–3 phase 2 and cohort studies up to 1000 individuals… No large phase 3 trials assessing vaccine efficacy on symptomatic illness of heterologous versus homologous strategies have been reported. These need to be urgently conducted.”
Indian Scenario
In India, although ICMR has found the mixing of Covishield and Covaxin safe, experts also advise to not use mixing randomly. It should rather be based on various issues. What are the correlates of immunity (humoral, cell mediated or both), which vaccines induce predominantly what kind of immune response, what is the correct sequence to elicit these responses, what should be the dosing interval between two prime and boost platforms, and durability of the immune response. Indian government has not yet allowed mixing of vaccines. As per the chairperson of Covid-19 working group under the National Technical Advisory Group on Immunisation (NTAGI), Dr N.K. Arora, India may soon start testing the mix-and-match approach to COVID-19 vaccines. Studies are going on to see if a single dose or a dose followed by a booster shot works better or not.
Covishield and Covaxin are based on two different platforms—the former is an adenovirus vector platform-based vaccine, while the latter is an inactivated whole virus vaccine. Adenovirus vector vaccine consists of live adenovirus, which is altered to such an extent that it cannot infect the individual to whom the vaccine is administered. Similarly, inactivated vaccines also include disease-causing virus, or parts of it, whose genetic material is totally destroyed using heat, chemicals, or radiation.
Effect of Covishield and Covaxin Combination
Dr Vineeta Bal, former scientist of the National Institute of Immunology, says, “Covishield will trigger only an anti-spike protein response (and of course anti-adenovirus response). Covaxin, used as a booster in principle, should boost anti-spike response further and generate a primary response against all other SARS-CoV-2 proteins which are part of the Covaxin preparation.”
As for ICMR data, it shows that heterologous vaccination can indeed trigger an anti-nucleocapsid protein (N-protein) response due to a boost with Covaxin. Nevertheless, further data is required to make it clear that heterologous vaccination strategy using Covishield and Covaxin combination is safe and beneficial.
She added that mixing was discouraged for lack of supporting data from clinical trials.
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