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Sunday, May 09, 2021

Explained: Should the gap between Covid-19 vaccine doses be increased?

Amid signs of a vaccine shortage and rising Covid-19 cases, would it make sense to raise the gap between doses? Dr Gagandeep Kang, a leading vaccine expert, weighs in.

Written by Gagandeep Kang | New Delhi |
April 12, 2021 4:09:26 am
A senior citizen receives a shot of a Covid vaccine in Mohali last week. (Express photo by Jasbir Malhi)

Amid signs of a vaccine shortage and rising Covid-19 cases, would it make sense to raise the gap between doses? Dr Gagandeep Kang, a leading vaccine expert, weighs in. Edited excerpts from an interview to Prabha Raghavan.

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How do you decide the right time to give a vaccine?

It really depends on the vaccine. A lot also depends on whether you’ve had prior exposure — whether there are pre-existing antibodies. For example, when you give a live vaccine and you’ve had prior exposure… or if it’s a child and the mother’s antibodies have been passed through the placenta, then you’ll have an immune response that’s not very good.

It doesn’t matter so much for inactivated vaccines, but it matters a lot for live vaccines. That’s one of the reasons why we give measles vaccines so late — we expect the maternal antibodies to have disappeared by the time we immunise at nine months.

How do you decide the best interval between doses?

For vaccines requiring multiple doses, the dose usually induces an immune response about three weeks later, but it can take up to eight weeks or longer for the antibodies to mature and become fully functional.

If you look at the basic principles of vaccination, there is no maximum interval defined for vaccines. You have recommended intervals, but you can give a second dose at any time. At the same time… you don’t want to go less than three, preferably four, weeks between doses.

What are the benefits of a longer interval during a pandemic?

If increasing the interval gives a greater degree of protection, it’s worthwhile. The other (benefit) is if you’re in a situation of constrained supply and you know that a single dose of the vaccine gives you reasonably good protection. This way, you can protect more people quickly while waiting for production to catch up and then disburse the second dose.

Are there any drawbacks?

If the vaccines rely entirely on two doses to give you protection, and if incomplete protection allows for the virus to replicate and therefore mutate, that is a drawback. However, at the moment, we don’t know… that the virus is mutating in people with normal immune systems who have received only a single dose. Those are very difficult studies to do… It’s not that hard to induce mutations in the lab… it becomes quite difficult to be able to relate back exactly to human beings, who are way more complicated than experimental systems.

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Are governments adjusting the gap between doses?

Lots of governments have been doing so. For instance, Canada has done this for all of their vaccines. In fact, they’ve decided to go with a four-month interval. I think many countries have decided that there is enough evidence to show that, for the AstraZeneca vaccine (Covishield in India), increasing the gap between doses definitely gives better value. If you look at the effectiveness data in the single-dose studies from the UK, you can see quite clearly that one dose is working very well and that it’s perfectly fine to lose the second dose for at least 12 weeks. More people in the UK are getting their second doses of vaccines only now, but you’ve already started to see a decline in deaths as an effect of the first dose.

For other vaccines as well, many countries have increased the gap between doses, but some countries that don’t have a shortage of supply have not. Now, is this going to be the perfect approach? We do not know, but I think it’s very unlikely that we’ll find that, in real life, the delayed dosing will significantly decrease vaccine effectiveness.

Should the gap between Covishield doses been longer than 8 weeks?

I was hoping for 8-12 weeks, but this is something at least. If you look at the affinity maturation of antibodies (a process where the immune system generates antibodies with an increased affinity for the antigen), that really starts to kick in only at 56 days, based on the studies that AstraZeneca has done.

I don’t agree with the government’s argument that an interval longer than eight weeks will not be as beneficial. I think increasing it beyond eight weeks makes a lot of sense, based on what we know. Now that we have a shortage of Covishield, there is even more reason to go for a longer interval.

The point is the WHO has recommended it as well. The government is making the argument that the AstraZeneca studies are very poorly done, that there isn’t enough data, these are all bad clinical trials, etc. But, if you’ve got data that shows that it is not unsafe, and that it may increase benefit, then, to me, it makes sense to use that data, especially if it can maximise coverage in your population.

Now, we also have data from the AstraZeneca trial in the US and South America that shows that you get 76% efficacy with a four-week interval. Does this mean that we could push it to 86% or 90% by increasing the dosing interval? It’s a more marginal benefit than we saw with the UK study, but it would still have some benefit. We don’t clearly know what the optimal interval is. It looks likely that it’s longer than four weeks, and I think we should give it a shot… We should also be doing a vaccine effectiveness study to look at the real world impact of different dosing schedules.

Can waiting longer for the second dose of Covishield increase the risk of infection?

As far as the argument that increasing the dosing interval for Covishield could lead to breakthrough infections is concerned, there is no data so far that proves you will get a greater number of breakthrough infections that result in disease comparing 4-, 8- or 12-week intervals. Data from the first three months of vaccinations in the UK is all based on a single dose — what we’re seeing there is good protection with the first dose.

Should the dosing interval for Covaxin also be increased?

I think it’s worthwhile for us to do this study. But, in general, inactivated vaccines do better with shorter intervals and might need more doses. So, whether Covaxin needs two doses or three, or a booster at some later stage is a question. All of these approaches are easy ways of trying to maximise protection, and these studies should be done. All studies would be a lot easier to do if we knew the correlate of protection (a marker that a person is immune). Right now, we don’t, but I’d be happy to go with the neutralising antibody response and see what maximises the neutralizing antibodies and see how that goes. It’s a substitute. It’s not perfect, but it’s something.

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