Given that we now have data showing three vaccines based on the spike protein that are working, it's likely we will also have other vaccines that are able to deliver the spike on any platform that will also work.
The last two weeks have seen a string of encouraging results from coronavirus vaccine trials. What do these findings mean, what questions remain, and what does India need for a mass vaccination exercise? One of India’s leading medical scientists, DR GAGANDEEP KANG, addresses these issues in an interview to PRABHA RAGHAVAN.
How surprising are the findings announced by Pfizer, Moderna and Russia that their respective vaccines have over 90 efficacy%?
All these vaccines offering protection at a high level was surprising because, with mucosal infections, you usually see less protection than for infections at other sites. Influenza vaccines, in a good season, offer about 60%, and this can be much lower when the strains are not matched. If we look at enteric (intestinal) infection vaccines, they can be 85-90% protective, but not in all parts of the world. With parenteral (non-oral) vaccines for a mucosal infection, one example we have is the polio vaccine — you can give an injectable polio vaccine, and it’s pretty good at preventing disease, but it doesn’t really protect against the mucosal component, which is infection of the enteric tract.
I don’t think we expected these vaccines to perform as well as they are. As we follow them for longer, the efficacy is not going to be maintained… These are early results, when the immune response has just been made. That said, for a reasonable timeframe, I don’t think the rates are going to decline incredibly.
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What does it mean to have an efficacy rate of over 90%?
Let’s start with a very simple design, which is a 1:1 randomisation. This means half the people will get the vaccine and the other half will get a placebo. If we’re looking at a vaccine trial with 20,000 people in this design, 10,000 would be vaccinated and 10,000 would not.
Let’s say 10% of people would normally get the infection with a very high attack rate. So, of the 10,000 people who have not received the vaccine, 1,000 people will get the disease within a defined period. Now, we also have 10,000 people who have received the vaccine. In them, if the vaccine does not work at all, we will get 1,000 infections, because 10% will get infected. If a vaccine has 50% efficacy, 500 people will get the infection and, if it has 90% efficacy, only 100 people will get infected.
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What do these results say about the effectiveness of targeting the virus’s spike protein?
The fact that we have two, maybe three, vaccines based on the spike protein that are working, and that they are on different platforms, is encouraging. The understanding was that, because the spike is responsible for attachment to the cell, if there was a way that we could block the spike, then that would allow us to be protected from infection. So, given that we now have data showing three vaccines based on the spike protein that are working, it’s likely we will also have other vaccines that are able to deliver the spike on any platform that will also work. Whether it is 85%, 90% or 95% efficacy is neither here nor there — they will likely work, so this is good news for the vaccine field.
After the information released by these firms, what questions remain?
Will it work in younger people? Will it work in people who are immunocompromised? Are these vaccines you can give to pregnant women? What would their safety record be? How long does protection last? What does the immune response look like? What is the B-cells component [a B-cell is a type of white blood cell that helps create antibodies against a pathogen while it is infecting the body]? What’s the T-cell component (T-cells are types of white blood cells that are part of the body’s long-term immune response against a virus, actively seeking it out to destroy it]?
We have some of this data from the phase 2 studies, but the detailed look at immunology so far is in small numbers. It’s good to see validation of the vaccines in different populations, but we also need to learn more about the safety issues — RNA, for instance, is very inflammatory. We saw there were more reactions in the people who got the highest dose in the Moderna trial, for example, and that dose is not being used for further studies. 📣 Express Explained is now on Telegram
The efficacy information released by these companies are just headline numbers in press releases. We haven’t seen the actual data, so we can’t say what protection looks like. Companies are going to have to publish this data and submit it to the regulators.
Earlier, experts said a vaccine with 60-70% efficacy was desirable. How desirable is this cut-off now?
If you have 90% efficacy, and it lasts six months versus having 60% efficacy that lasts 10 years, which one would you pick? We can’t make decisions based on press releases. It’s encouraging information, but we have to wait for the full datasets, analyse them, and then decide how we want to move forward.
It is about the performance characteristics of the vaccine and the goals you are trying to achieve.
If we look at other vaccines… In the case of the oral polio vaccine, immune responses in low — and middle-income countries are much lower than for injectable polio vaccines. But, a decision was made to go with oral polio vaccines, because they are much easier to deliver to the population.
You wound up using more doses of oral polio vaccine, but you still got to the same goal of trying to eliminate the disease from the country. Now, we are trying to eradicate it by combining oral and injectable vaccines.
The Pfizer and Moderna vaccines don’t seem feasible for developing countries. What sort of vaccine would be better suited for India?
A good vaccine for India is an affordable vaccine that can be made in large numbers and delivered easily — preferably as a single dose. It should give long-term protection — I would like lifetime protection. We don’t know this will happen, but one dose eases the burden on the immunisation programme, because you don’t have the problem of needing to track the person down for the second dose.
We don’t have a vaccine as expensive as the AstraZeneca vaccine (Covishield) in our programme at the moment, and that’s at $3 a dose — the lowest price announced. It still means you need $6 just for the vaccine and more to deliver it in campaign mode. If you’re talking $10 per person per set of vaccination, that already makes it the most expensive vaccination program this country has ever had — at the individual, per person, cost and not just in terms of the number of people that would need to be immunized.
If we’re talking about national programmes and immunising everybody in the country, we are going to need something under a dollar a dose, preferably under 50 cents.
These are the kinds of things second-wave candidates should be aiming for.
Do any strong contenders fit the bill?
There are many companies working on different vectored vaccines — measles, VSV — that have the potential to be single-dose vaccines, though they are a bit further behind in development. In any case, we should be thinking about second-wave vaccines. Given the results we are seeing with spike protein here with an RNA vaccine, it’s feasible that, even if we had protein vaccines with an adjuvant, they would work equally well.
Something like what Bio E is doing with the Baylor College of Medicine, which is a protein-based candidate, might be a good way to go. Assuming that they can move rapidly through testing, you could be looking at a vaccine that will have a readout in 2021. Janssen’s vaccine is an adenovector vaccine which is planned as a single dose, because it’s a replicating vector. Bio E is also working with them on this, so that’s potential too.
How soon can a first-wave vaccine be realistically expected in India?
The first-wave vaccines that are going to come out quicker than others [globally] are the two mRNA candidates and probably AstraZeneca’s.
Concerning ramping up of manufacturing with AstraZeneca — though we’ve heard about how they’re going to make hundreds of millions of doses (of Covishield) — [Serum Institute of India CEO] Adar Poonawalla said this month we have 40 million doses and, in subsequent months, we will have more. That’s not the message we got 3-4 months ago, when we were told about hundreds of millions of doses being made every month.
I think initial availability is going to be limited and the trickle will become stronger as production increases… we are not really going to have serious amounts of a vaccine even with the successful candidates for another three to five months.
That’s time to get logistics for delivery together, because I don’t think we are as ready as we should be… I don’t think I’ve heard enough about the planning to know most problems have been anticipated and the rollout will be smooth and as high volume as is being projected.
What more should we know to get a better sense of how the government is geared up?
You would need to start communicating with groups likely to be vaccinated early. The government could put out a plan telling us this is how sequencing of vaccination is going to be done — in not just the big broad term of “these are the 3-5 categories (of priority groups that will get the vaccine first)”, but also how they are going to operate within states.
The big picture is at the Centre but, at the state level, there has to be a delivery mechanism and clarity. We hear you’re going to have healthcare workers, but is it private or public healthcare? What’s the sequence? How do you break down healthcare workers? And, in our country, can you deliver to all healthcare workers around the country at the same time or will some states be prioritised?
We’ve never seen this scale of activity before, so it would be reassuring to have a public plan for how this is actually going to be done.
The Pfizer and Moderna vaccines, both mRNA, have different storage temperatures. Is it possible, then, to develop an mRNA vaccine that can be stored at warmer temperatures?
Every mRNA vaccine is different. The sequence that codes for the stabilised spike may be the same, but when you’re making a vaccine which is either enclosed within a lipid nanoparticle or integrated with it, you’re going to have different levels of stability. Just because it’s mRNA, doesn’t mean that every vaccine is equivalent.
Gennova Biopharmaceuticals (which is also working on an mRNA vaccine) is planning to make a vaccine that can be stored at 2°C to 8°C. CureVac [of Germany] is also working on a 2°C to 8°C formulation. Even Pfizer is planning to modify its formulation, but it will take them a couple of years to get to that point, which is not surprising, because Moderna has been in the mRNA game for a long time, while BioNTech and Pfizer’s tie-up was fairly recent. It takes time to develop these more stable formulations.
Are vials and syringes still an issue?
Yes, they are. Particularly, if you have a need for cryo-vials, then you need special kinds of glass.
I’ve mentioned auto-disabled syringes before, and that is a rate limiting — not for manufacturers, but for the immunisation programme. Glass vials certainly are (a challenge), but I don’t know whether there are even enough rubber stoppers and the aluminum foil that goes on top of these injection vials. Those are significant issues. And then, if you are going to have vaccine vial monitors (VVMs) to monitor the temperature of vaccines and excursions — those little printed stickers — there’s only one company in the world authorized to make them. Companies using VVMs will have to get in line for them.
Even for making the vaccines, they are made out of different kinds of chemicals. You are going to have another problem here, and that’s one of the issues with the mRNA vaccines — are there going to be sufficient nucleotides to manufacture the RNA on the scale that people want? You will have to break each vaccine down into its components and look at the supply chain. Glass, rubber stoppers and syringes are common for all vaccines, but the actual composition of different vaccines really depends on what the formulations are.
How has vaccine development changed from the time of rotavirus to this pandemic?
In the case of the rotavirus vaccine, the technology used is the same as the oral polio vaccine. When we were looking at the rotavirus vaccine, we expected, from the polio experience, to have lower efficacy in developing countries. The phase 3 efficacy trials we did had a lower bound of efficacy of 20% — the vaccine would have been considered working if it met this 20% protection mark. It finally wound up being 55%, and that is no different from the performance of any other oral rotavirus vaccines in similar parts of the world.
The challenges we will see in the future with SARS-CoV-2 vaccines are what we saw with our rotavirus vaccine. Essentially, if these Pfizer and Moderna vaccines get licensed — and they are pretty close to being able to apply for licensure soon — then those vaccines might become the standard of care, which means any future vaccine trials cannot have the standard placebo-controlled design and have to be designed as non-inferiority trials, which then makes the study very large.
In the case of the rotavirus trials, the Rotarix and Rotateq vaccines were already in the market, and we had to then have discussions with ethicists to see whether a placebo-controlled trial was needed. Finally, it was decided it could be done under certain special circumstances. Although the multinational vaccines were licensed in India, they were not recommended as part of the national immunization programme. The study team also made a commitment to ensure every child would be looked after as well as possible for the entire duration of the trial and followed up, whether that was an illness related to what the vaccine was trying to prevent or not.
I think these are the kinds of issues that we will see in the future with the entire field of SARS-CoV-2 vaccines. Where manufacturing of these vaccines is concerned, with mRNA, we have no idea what the issues might be once you make large scale batches. Failures of batches are very much a fact in the development of vaccines. Whether that will happen with mRNA and if it us a failsafe, easy to use technology are aspects we really have no clue about yet.
What new challenges does this pandemic present in vaccine development?
Right now, we don’t know, because we haven’t made large batches of vaccines with the newer technologies. So, it’s very hard to say that it’s going to work, and even with the older technologies, every programme of manufacturing has to be optimised. That’s why what are called Chemistry Manufacturing Controls are very important for regulators.
We talk about clinical efficacy all the time, but the process of vaccine development, assessment of the vaccine quality also is a long process vaccine manufacturers undertake, and every programme is different. Even if you’re using the same platform to make a new vaccine, you can use your learning for prior experience, but the tweaking will have to be individual to that programme.
DR GAGANDEEP KANG, Professor at Christian Medical College–Vellore, is one of India’s leading medical scientists. Dr Kang’s work on vaccines includes a key role in development of India’s indigenous rotavirus vaccine. She is the first Indian woman inducted as Fellow of the Royal Society. She was recently Chair of an ICMR panel on Covid-19 drugs and vaccines.
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