In August, the Indian drug regulator (DCGI) granted an emergency use approval for Zydus Cadila’s DNA vaccine for use in adults and children aged 12 years and above. Recently the Subject Expert Committee of DCGI greenlighted Covaxin for children above two years. The vaccines are yet to be introduced in the national vaccination programme. The National Immunization Technical Advisory Group (NTAGI) Chairperson Dr. N.K. Arora had said children with comorbidities will be prioritised to receive the vaccine “immediately and healthy children can be immunised subsequently”. In an email, immunologist Dr. Satyajit Rath, formerly with the Delhi-based National Institute of Immunology and Dr. Chandrakant Lahariya, Physician-epidemiologist and vaccines expert discuss who needs the vaccine first and if healthy children need to be vaccinated.
Which subgroup of children and adolescents needs to get the vaccine on priority — the immunocompromised, adolescents, or those with comorbidities?
Dr Satyajit Rath
Satyajit Rath: This issue is somewhat complicated. Firstly, immunocompromised individuals, children or adults, may not, in fact, respond effectively to vaccination either. So simply saying that they are a vaccination priority is likely to be inadequate, and we need evidence (which we do not have) about what vaccination schedules might work well for them. Secondly, while it is true that children with the known comorbidities (which are not common among children) ought to be a priority for vaccination, there is another issue as well. In some instances, the nature of severe COVID-19 illness may be somewhat different in children (the so-called MIS-C), and we do not know, as far as I am aware, the predisposing factors for that. That all said, it is probably best, all other things being equal, to prioritise school-going children over younger children for vaccination, since that might have somewhat more of an effect on the spread of infection.
Dr Chandrakant Lahariya
Chandrakant Lahariya: The current scientific evidence does not support vaccination of all healthy children. There is some experience and data now on use of a few specific COVID-19 vaccines in 12-17 years. Since COVID-19 vaccines are developed using different platforms, each needs its own data. Of the two COVID-19 vaccines being considered for use in the children in India, have so far been used only on 500-1,500 children in the trials. In fact, one of these vaccines — the Zydus vaccine (ZyCoV-D) — has not been used on any age group outside the clinical trials. Scientifically, we know that vaccines may have some the rare adverse events which can only be identified after their programmatic roll-out and effective adverse events following immunisation (AEFI) surveillance.
We also know that the efficacy of these have been tested against moderate-to-severe COVID-19, which are relatively low in children. Then, the experience of COVID-19 vaccines already in use in adolescents indicates that the risk of rare adverse events is relatively higher in adolescents than in adults. Putting these two together, there is less benefit and higher risk in vaccinating children and that’s why we should wait for more safety data to be available to recommend COVID-19 vaccination beyond the high-risk groups in older children.
Which high-risk sub-group to start with and which age sub-group has to be determined by review of the hospitalisation and mortality data from COVID-19 pandemic in India. That will provide fair insight where to start. Based upon such available data, starting with the high-risk children in 16-17 years could be one approach. Once full vaccine coverage of, let’s say 70-80% in that sub-group is achieved, it can be opened for high-risk children aged 12-15 years. Even the list of what constitutes high risk children should be based upon evidence and could be dynamic with possibility of inclusion of more conditions, once evidence is available. With available evidence, I don’t think India should consider vaccinating any child younger than 12 years before early next year.
Do we need small trials among children and adolescents with comorbidities before deciding to vaccinate them?
S.R.: I worry that we tend to treat vaccines as drugs, which they are not. Their safety certainly needs to be tested carefully with evidence. However, the comorbidities we are talking about are more relevant for the severity of COVID-19 disease, and not so much for vaccine safety, I think. So, yes, we need standard safety trials of all vaccines in children of appropriate age groups before approving and deploying them. But I do not think that large numbers of individuals with comorbidities need to be part of these safety trials.
C.L.: There is no need for additional clinical trials. The purpose of additional clinical trials in children is to examine dose tolerability, immunogenicity and safety. That much information is available. We need to remember these findings are always interpreted with findings of full trial in adults. However, the rare adverse events which cannot be picked by the clinical trials but can be different and at a higher rate in children, is what is of interest to experts involved in decision making. This requires the use of vaccines in programmes and a stronger and sensitive adverse-event reporting system which can capture such information.
Which comorbidities in children and adolescents make them more susceptible to severe disease and even death?
C.L.: The selection of comorbidities as criteria for vaccine eligibility is going to be complex and challenging. It has to factor in the operational feasibility, where the process to show comorbidity is not far too complicated. I think, in the beginning, it could be a narrow list of conditions to define high risk children, which can be expanded with further deliberations. Some such as immunocompromised children, those on long term therapies and illnesses and diabetic are common considerations. Easiest way to arrive on such a list is to use the available COVID-19 hospitalisation data and analyse which children required hospitalisation and what were the common morbidities they had.
Are there sufficient data for disease severity and long COVID in children (12 years and younger) and adolescents without comorbidities? In the absence of such data, should India be in a hurry to vaccinate them?
S.R.: There is evidence that even very young children can indeed suffer from severe COVID-19. I am not sure what would be considered “sufficient” evidence. Since there is no substantial risk in giving vaccines, once safety-tested with standard protocols, I am not sure why we would think in terms of “hurry” in vaccinating children. Vaccination, after all, provides not only the individual gain of protection from severe illness but also of reduction (however modest) in the magnitude and duration of virus spread to other people.
Are vaccines needed for healthy children and adolescents, especially since Covaxin supply is still limited and millions of adults are yet to be vaccinated with first/second dose, and nearly 60% of children have already been naturally infected?
S.R.: Well, vaccines are certainly needed for everyone. As an aside, again, I do not think that guesses about the proportions of people in various groups already infected/vaccinated, which depend on sero-surveys, are well founded. Many if not most of these sero-surveys have been modest in size, yet we are assuming that they correctly reflect reality. Also, we tend to assume that this percentage (60%) is uniformly seen in all children across the country, which is quite unlikely. Finally, I continue to think that vaccination carries value even for previously infected individuals. So we need vaccines.
Our inability to provide them adequately does, however, create a depressing situation of having to make priority choices, and in this sense, adults are clearly a higher priority for COVID-19 vaccination.
C.L.: The healthy children in India do not need vaccination, at least not at present. It is not about vaccine availability alone. India has reached a stage where there is more COVID-19 vaccine supply then demand. However, just because a country has more availability, it should not start vaccinating children. At the same time, that does not mean healthy children would never need COVID-19 vaccines. They may, in future. As an example, if a new variant emerges which causes moderate to severe disease in children at a rate higher than at present, then we may have to vaccinate healthy children.
The Zydus vaccine uses a novel vaccine platform, and outside the trial, the vaccine has not been used for vaccinating adults. Should such a vaccine be allowed to be used on adolescents without large-scale use in adults first?
S.R.: Since I do not think there are extraordinary risks with either the platform or the route of administration, I find the standard regulatory processes sufficient for determining whether to approve vaccine usage in children.
C.L.: It can be, at least theoretically. However, parents and people need to understand that none of the countries had rolled out vaccines for any subgroup of children without data being thoroughly examined and reviewed by the experts. None of the COVID-19 vaccines has been used in children in any country before millions of shots were administered to adults. There has been a time lag of around six months or longer use of a vaccine in adults before use in children. This was the approach even when there was a high rate of disease transmission in those settings.
While the FDA has granted an emergency use approval (EUA) for Pfizer vaccine for children in stages beginning with adolescents, the Subject Expert Committee has greenlighted Covaxin for all children above two years and the DCGI has granted an EUA for Zydus vaccine for those older than 12 years including adults. How prudent is this approach by the SEC and DCGI?
C.L.: Every country has their own regulatory approval approach and the criteria to give such authorisation. What we need to remember is that the regulatory approvals are focused upon data from clinical trials, examining whether the protocol was followed and if it meets pre-defined safety, efficacy and other agreed criteria. However, what is important to understand is that the licensing of vaccines is completely delinked from programmatic use of vaccines. Licensing does not mean it should be rolled out in a program. The decision on the second part is taken by an independent group of experts, who recommend vaccine introduction based upon a completely different set of considerations such as burden of diseases, risks and benefit, operational feasibility. They can and they do use data from other countries as well, to make a decision and even demand for limited roll-out and/or more data before decision making. What we need to remember is that the number of participants in the clinical trials of COVID-19 vaccines in children have been around one third of what other countries have done and that is limited data to consider full-fledged roll-out in children. When it comes to vaccinating kids, there is no such urgency as it was for the adult population, who are at higher risk. The decision to vaccinate kids has to be based upon calm assessment of scientific evidence, with use of as much data as possible, even if that means a few more weeks or months of waiting.
