According to experts, mixing of vaccines is not new and this strategy has been tested out with the vaccines like diphtheria, tetanus and pertussis vaccine. In a recent study, the Indian Council of Medical Research (ICMR) has made some important observations. Eighteen patients who were given Covishield as the first dose and Covaxin as the second dose were studied. They were given the doses at a gap of six weeks. Further, 40 patients who received both doses of Covishield and 40 patients who received both doses of Covaxin were studied. Overall, the mixed group had higher antibodies and had no significantly higher side effects.
Similarly, a UK study called Com-COV, which analyzed combinations of the same two vaccines, found that people in the mix-and-match groups experienced higher rates of common vaccine-related side effects, such as fever, than people who received two doses of the same vaccine. Globally, immunologists and experts believe that the ability to mix and match COVID-19 vaccines could have benefits.
Under the lens
Vouching for the mixing of vaccines as beneficial, Dr T. Jacob John, Clinical Virologist, Microbiologist, Christian Medical College (CMC), Vellore, said, “Mixing of vaccines has advantages if you have two doses of vaccine A and two of vaccine B. If you give A followed by B or B followed by A, higher antibody levels are obtained. It is a minor advantage, but if the antibody (virus neutralizing) against the Delta variant is high, that is a major advantage.”
Dr Chandrakant Lahariya, Physician and Epidemiologist and Public Policy and Health Systems expert, said, “We don’t know enough yet. Though, there have been limited and small-scale studies done on mix and match of vaccines, which have found the approach to have a similar safety profile and generate higher levels of antibodies. However, there is a need for bigger studies and evidence from real-life situations to get more information and better understanding.”
Elucidating a few advantages, Lahariya informed that some of the early studies on the mix and match of vaccines have indicated production of higher levels of neutralizing antibodies; it might provide better protection from some emerging variants. In addition, it may simplify the vaccination drive and people may not have to wait for the same vaccine and can take other available vaccines. It will also allow flexibility to get a different shot to individuals traveling abroad. Besides, higher neutralizing antibodies may mean longer duration of antibodies and the need for booster shots may be delayed, if and when needed. This is clearly an area which needs more studies and scientific evidence.
Informing that there is science behind why Covaxin after Covishield works better, Dr. M S S Mukharjee, Senior Interventional Cardiologist and Director of the Cardiology Department, Medicover Hospitals, said, “The mixed vaccine strategy is better, comes from a small hypothesis-generating, surrogate (meaning antibodies were measured, not clinical data of how many infected or survived post-vaccination) study. It has to be corroborated in a larger and clinical study, for which the DCGI has already given approval. There is science behind why Covaxin after Covishield works better.”
Adding to it, Mukharjee also said, “To understand this, first we need to know that Covaxin is an inactivated virus vaccine and Covishield is a viral vector vaccine. Viral vector vaccine has a coronavirus component and a vehicle to carry that component, which is another virus: “the chimpanzee adenovirus” (Ad26). The vaccines are given in two doses because the protection offered by each dose of the vaccine is suboptimal. The immunity elicited after the Covishield vaccine has two components. The important part of the immunity is towards the component of coronavirus. The unwanted portion of the immunity is towards the adenovirus vehicle of this component. This immunity against the chimpanzee adenovirus is detrimental for the efficacy of the next dose of Covishield as this may neutralize the vaccine before the important corona viral component is expressed. If the second dose is Covaxin instead of Covishield, then this detrimental immunity against Ad26 doesn’t matter as Covaxin doesn’t contain this adenovirus.”
Dr John, referring to the UK studies, said, “The study showed that AstraZeneca and Pfizer vaccines, given one after the other, results in much greater virus neutralizing antibody levels than the same vaccine’s two doses. The small Indian study with Covishield and Covaxin shows the same trend. These are observations without the immunological mechanism explored or explained. Vaccine efficacy cannot be measured but we can measure a surrogate, by way of antibody titres. Why there has been no explanation yet, as all vaccines are spike protein vaccines, with slightly different antigen configuration. The immune system recognizes such minor differences and responds more vigorously.”
As several studies are currently underway for the mixing of vaccine shots, the experts also inform that it’s not the time to decide on implementing the different dosing regimens on the masses.
Safety assessment of vax mix – Need of the hour
Experts urge for a detailed study before the mix strategy is implemented to the masses as COVID-19 pandemic is still a puzzle. Even after the completion of 20 months from the first case, numerous variants are emerging and the chains of transmission are continuing.
Pointing out that the ICMR study is actually a very small sample to conclude anything other than some initial evidence for a detailed study, Lahariya said, “There is not enough scientific evidence about the mix and match of COVID-19 vaccines being used in India. I would suggest the technical experts and government to wait for the results of other studies which are being planned, before making any recommendation. I think that is what the COVID-19 vaccine expert group is likely to do. There is one study on mix-and-match being planned by CMC Vellore and I am sure there would be a few more from other settings.”
Outrightly regretting that the government should consider the mix and match of vaccines now, Dr Jacob said, “No, not now. However, the government can relax the strict application of the current rule of both doses of the same vaccine. One, for travel purposes, as Covishield is internationally approved with EUA. So, if a person had first dose Covaxin (not approved to travel to a country), the person should have the freedom to choose the option of next dose Covishield. If someone had an adverse reaction to the first dose (far more common with Covishield than Covaxin) and if it was allergic or blood clotting, etc., the next dose must be the other vaccine, Covaxin — today such option does not exist.”
Dr. Mukharjee, said, “The government should consider the studies of mix and match vaccines. It shouldn’t approve of these strategies without actually testing them. The reason is that the Covishield and Covaxin seem to be effective against the symptomatic infection by approximately 75 percent only. Against the Delta variant, the efficacy of these vaccines may even be lower. The mixed vaccine strategies may perform better in this regard. The hope was raised when the ICMR study results were published, but this has yet to be proven in a larger study.”
As per the epidemiologist, microbiologist and other healthcare experts, as of now, COVID-19 vaccination schedules are only priming doses — the immunity induced by one dose to another is expected to wane.
Vaccine efficacy developments
Explaining the efficacy of vaccines, Dr Jacob pointed out that there is a difference between vaccine efficacy (in clinical studies), vaccine effectiveness (after rolling out a vaccine) and vaccine immunogenic response (serum antibody and T-cell immunity). Over time, the immunity wanes (both efficacy and immune response). If waning applies to the mother variant (with which vaccine was made), it will be more likely with other variants also.
“It is known that the antibody levels after the vaccination reduce over time. But the protection against the viral illness may still be there because of the cell-mediated immunity, which is another form of immunity that our body has. But the fear of a reduction in vaccine efficacy with time is driving the research into the booster doses. Regardless of the time after vaccination, a vaccine may be less effective for a new variant than the original variant against which it was developed. That’s why we may need boosters, but it makes more sense to have custom-made boosters against the new variants, rather than taking the previous version of the vaccines as boosters,” Dr. Mukharjee added.
Highlighting that COVID-19 vaccines are first-generation vaccines, Lahariya, said, “As it happens with all vaccines, even after vaccine licensing, the researchers keep working on improving the vaccines, either through adjuvants or other mechanisms. The next generation of COVID-19 vaccines would be better in safety as well as effectiveness against the existing and emerging variants. Therefore, there might be minor variations in effectiveness against emerging variants. However, we should not worry too much about future scenarios because if variants emerge, the vaccines will also be improved.”
“The level of antibodies declines over a period of time and the decline is after four months of vaccination. In fact, that is true about natural infection as well. However, we also know that there is no linear relationship between the level of antibodies and protection. Whether reduced levels of antibodies are associated with reduced protection, we do not know yet. What is known is that beyond antibodies, there is a cellular response as well. Though the level of antibodies declines, if we need a demand booster shot, we need to have more scientific evidence,” Lahariya said.
Millions of lives have already been lost due to the pandemic. Scientists are now exploring the benefits of mixing vaccines, as it can combat different variants so as to give a broad collective immunity. Experts, though, alert that periodic vaccine booster shots would be necessary for long-lasting immunity to overcome the waning immunity.