WHO on the checks & balances for COVID-19 vaccines

As Russia approves a vaccine to fight against SARS-Cov-2, it is useful to note what global authorities, including WHO have said about the checks and balances in vaccine development in the context of COVID-19.

Here is what Dr Soumya Swaminathan, WHO Chief Scientist has had to say about the processes around vaccine development in a recent conversation online. This was first broadcast by WHO on July 24, 2020, as an interaction on social media, moderated by Dr Margaret Harris. The following has been lightly edited for length and clarity. [There have been developments since, see Draft landscape of COVID-19 candidate vaccines, updated by WHO earlier this week.]

Q1. Can you tell us where we are with the vaccines? We understand, some vaccine candidates are coming into human trials. What is the latest update on vaccines? 

We have been involved with the vaccine development efforts as well as with the overall efforts on research and development on all aspects of the coronavirus, right from the beginning of the pandemic in January [2020]. One of the really extraordinary things that I have observed is the speed at which the science is moving, the speed at which we are learning new things about the virus and the speed at which we are developing vaccines. 

As of today, we have over 200 candidates at some stage of development. As you know, vaccine development is normally quite a lengthy, complex and laborious process – starts first with developing what we call a candidate vaccine which can be of many different types. You can have an inactivated virus where you take a whole virus and inactivate it by using some chemicals so that it cannot replicate. That is then purified and made into a vaccine candidate.

Or you can get take just a part of the virus, the protein – in this case the spike protein – that is supposed to induce the immunity. The spike protein can also be created in different ways – you can use recombinant technology to create it; you can extract it from the virus; you can create virus-like particles. 

Then, you have another form where you can use another virus as a vector, so you can use a measles virus or you can use a varicella virus, or adenoviruses. Many of these viruses have been used in the past. So you can put the genetic sequence of this virus of interest – in this case the SARS-CoV-2 – on to that viral platform and then inject that. So that it takes the genetic material into the body.

And most excitingly, this time around we have two completely new platforms that have never been used in humans before – RNA vaccines where you are straight away taking the messenger RNA, or the RNA of the virus injecting that into the body. That, then has to go into the cell in the human body and then the messenger RNA gives the message to the human cell to start making the protein of the virus, which then induces the immune response. We also have DNA vaccines. So, these are two novel platforms, the others have been used before for different diseases. 

So what scientists were able to do is, as soon as they saw the genetic sequence of the SARS-Cov-2 virus, which was made available by Chinese scientists on January 11th though a public platform called GISAID, they took the genetic sequence and started creating these vaccines first in the lab where it goes to small animals like mice, hamsters and guinea pigs. Then it normally goes into larger animals like non-human primates such as monkeys before it comes to human beings. In this case of course, a lot of these steps were accelerated. 

If you have been working with a vaccine platform that you have used before for vaccines of other diseases then it is relatively straight forward to move into human trials, because you have had experience before.

So the first phase I trial started within about 8-10 weeks of the genetic sequence of the virus being made public. Today we have about 24 vaccines in human clinical trials at some phase or the other – phase I, II and III [This number has now been updated to be 26]. And, overall, over 150 which are at some stages of pre-clinical development, many of them approaching clinical development in the later part of this year. So, we have a very robust pipeline of vaccine candidates which is excellent. Because, normally the success rate of a vaccine is about 10%. Therefore, the more candidate we have the more opportunities we will have for success. 

Q2. Can you tell us the difference between the phases of the clinical trials and why they all matter. The significance of a Phase III trial. 

So, phase I is the first in human testing. What’s normally done is that healthy adult volunteers are selected. And this vaccine is given, sometimes in different doses to between 30 to 50 people usually. The ideal phase I is really to look at the safety of the vaccine, to make sure that there is nothing unexpected.

Then you go into Phase II, which is usually around several hundred people, could be up to a thousand or so, where you are looking at safety at a larger group of people. But you are also now starting to look at immunogenicity – the capacity of a vaccine to elicit a strong immune response. You are drawing blood from these volunteers at different time points studying the immunogenicity as well as the safety. This is very critical because once you establish safety in several hundred volunteers, you go into phase III. 

Phase III is the most important trial, because that’s the one that gives you the answer about whether or not the vaccine protects you from the disease.

And in this phase, there are normally tens of thousands of volunteers that are needed. These are people who are otherwise healthy but are at risk of contracting this infection. Half of them are given the new vaccine, and the other half are given either a placebo injection or a standard vaccine – it could be a hepatitis vaccine or a meningitis vaccine or some other vaccine that is already used in humans. 

Then, these people have to be followed over a period of months to see how many develop COVID-19. And then you compare how many in the vaccine group developed COVID-19 and how many in the placebo group or the control group did. And look at the difference. Of course, you expect if the vaccine is effective you will have far fewer infections in the vaccinated group and that’s what we call the efficacy of the vaccine. We would like to see as high protection, or as high efficacy as possible. 80%, 90% would be fantastic – the minimum would be, say, 70%. The FDA has said that minimum absolutely bare minimum efficacy of a vaccine should be 50%.

You also have the opportunity to study safety in much larger groups of people. With tens of thousands of people, even relatively rare side effects can be picked up. You also monitor them by taking blood at periodic intervals, so you are also studying the antibody responses. The follow-up usually continues for a couple of years because you want to see how long this vaccine will protect you. So, phase III vaccines usually take time, they are done in large numbers of people, they need a lot of follow up, they are complex. 

In this case, the world is in a hurry and this is a pandemic. It is possible that if you get an answer, say, within six months – if you knew about protection, if you knew about safety, you would still continue to follow up people enrolled in the vaccine trial over a period of time. This would be usually two years, or may be even longer. You could look at six months and, say, is that good enough for me to move ahead. And this is something, regulators all over the world are discussing – what should those criteria be, that will enable a regulator to say – ‘yes, I am satisfied, this vaccine is protecting people, I can use it in the wider population.’ 

Then, there is something called as Phase IV, which is even after a vaccine is licensed and it is being used in the population you still continue to monitor and follow up the population over a period of time, till you are absolutely certain that the vaccine is safe and it is doing what it is supposed to do. 

Q3. Will WHO license vaccines, since it has a pre-qualification process? Or is it up to the different regulatory bodies across the world?

That’s a really good question. That’s why I mentioned why the regulators are playing such an important role. They are already discussing among their regulatory networks around the world. WHO’s regulatory department is also involved in setting those criteria. These criteria will help enable regulators to agree that these vaccines could meet such criteria. 

WHO does something called pre-qualification of vaccines. This is sort of a quality benchmark that WHO provides to vaccine manufacturers, based on which many global procurement agencies like Gavi, UNICEF, The Global Fund etc, would then purchase vaccines for mass distribution or donation to countries. But normally every country relies on their own regulator to license products for their country whether it is drugs or vaccines. So, you would still have to go through that process, but I think again in this case because of the urgency and because of the pandemic, that there is going to be a fair amount of harmonization so that this process can move quite fast. Normally these things take a long time and sometimes it can take years before a vaccine is developed and when it is being licensed and used in countries. So, it is really important that this step as well be compressed so that you are saving time without compromising on the safety and the efficacy aspect of the vaccine. 

Q4. Of the candidate vaccines you mentioned, that are in human trials, how many are in this last phase?

We know that there are three going into Phase III, perhaps a fourth one. The three that we know about is the Astra Zeneca vaccine, developed by the Jenner Institute in Oxford using the Chimpanzee adenovirus. Candidates we just seen the results from the results of the phase I/II study does seem to be safe, does seem to elicit antibodies and T-cell responses. That is very encouraging. 

We have also seen results from the mRNA Moderna phase I vaccine, as well the Chinese vaccine made by the company Can Sino, that have also published phase II results that show that volunteers developed antibodies against the virus. So, we know that all three of these is going to Phase III trials, all beginning in the month of July. 

We are also aware that there is a Russian candidate vaccine that will also be entering phase III trials. There are several others which are in phase I/II which will enter phase 3 trials in the next 2 or 3 months.  [Russia has since announced that it has approved a vaccine.]

Q5. Question on populations: will the vaccines be tested in older people, or those vulnerable in some countries? People of a different genetic makeup?

We know that COVID-19 has a particularly worse clinical outcome in older people and those who have co-morbidities. We also know that the older the individual, the less the immune system is able to recover, recuperate and react. So many vaccines actually don’t elicit the same kind of immune response in older people as it does in younger people, so I think it is really important to test that group. For most of the vaccine candidates in development, there is a plan. 

Usually the testing starts off with adults – 18 to 55. But many of these vaccine candidates are going down to test children from five years on and also to take test adults between the ages of 55 and 70. I think that’s definitely the need and also the plan to collect data in these different age groups. And I think there is also the need to include people who have diabetes or hypertension or other kinds of chronic diseases to see how they respond. 

It’s also important to do the clinical trials in places where you can answer the question you set out with. As I mentioned earlier, you need natural infection to occur in both these groups – the vaccinated group and the control group in order to compare. If a vaccine trial is done in a country which has successfully controlled the infection, it might happen that you won’t get enough infections. And then you don’t answer the question. So, this is why you see, that many companies are looking at doing their trials in different countries or in different parts of the same country so you also take advantage of the epidemiological movement of this virus. 

Q6.  Of course, we have got the timeline question – the question everybody wants answered. It could take six months to get an answer to the question about efficacy, but how long will it take for the regulators to decide to go ahead and for the scale-up of manufacturing, what sort of timeline are we looking at if indeed a vaccine candidate proves to be efficacious? 

Yes. All of these different steps as you mentioned…normally this would all happen sequentially. A company would first develop a vaccine and then they would go to the phase I, phase II, then phase III. Depending on the disease, phase III can take a long time. Then once they have the results from the trials, they would start scaling up manufacturing, apply for licensing in different countries and then start supplying the vaccine. It can take years sometimes. 

One of the things that we have set out to do along with our partners CEPI and Gavi – we are all working together on the vaccines pillar of the ACT accelerator. 

The idea is not only to fast-track the research and development of the vaccine but also to invest in manufacturing upfront. So, making companies actually set up those manufacturing plants in different parts of the world so that you can also scale up very quickly. Now, this of course is a risky proposition for companies because they do not know when they will get results from the trial, whether or not the vaccine candidate will be effective and whether or not they need that manufacturing plant. But because we cannot afford to wait, it is absolutely imperative that many of these candidates have that manufacturing capacity right now. If it is not used for this vaccine, perhaps it could be used for another vaccine. So that is on the manufacturing side and the scaling up for it. 

But there is also the preparation that countries need to do…the regulators need to be prepared for the dossiers that will be coming in. And the ministries of health that are actually going to undertake the vaccination programs also need to prepare. They need to have a clear plan, strategy, policy. They need to have the logistics in place – the cold chains and other suppliers. You need needles, syringes, refrigerators. And you need an engagement plan, depending on which segments of the population you are going to vaccinate. As you know, this vaccine, we are going to be targeting adults. Most countries have a vaccination program that targets children. It is a very unusual to be vaccinating large adult populations. So, no country does that at the moment.  So, for every country it is going to be a challenge. How are we going to reach people, how are these vaccination campaigns going to be carried out successfully. How do we get communities to understand, and for people to also start understanding and learning and being accepting of this vaccine. 

Q7. How do you buy in engagement from communities? Concerns on speed of developing vaccines, how does one know it is safe?

I think, that’s why communication is so important. I did say that while speed is important, it cannot be at the cost of compromising on the safety and the efficacy standards that one is setting for oneself. And so, it’s not the case that’s the first vaccine is going to be rushed through into injecting millions of people without having established the fact, whether it is really protecting you and whether it’s safe enough for use in large populations.

There are clear protocols, there are clear criteria to test those against. And the regulators are also watching very carefully. I think people can be confident that when regulators, the WHO and others say that the vaccine can be used for people to protect against COVID-19, that we would have seen sufficient data to be confident that this is the case. 

Having said that, you can always have a very rare side effect that is not observed during the initial clinical trials, even in tens of thousands of people. It could be so rare, that you could only start seeing it when you are vaccinating millions of people. So that’s why we continue what is called post-licensure monitoring or what is sometimes, called phase IV trial. Even when you are being fairly confident, when the regulators have licensed the vaccine for use, you are still following up for a couple of years, to make sure that there’s nothing that is going wrong, nothing that is rare and that can only be picked up, when you know, you are vaccinating large numbers of people. This could happen, we need to be aware. But it also means, that we look at the safety-benefit ratio of anything – whether it is a drug or a vaccine, you always have to consider the benefits and the potential risks, and take a call. 

So, everything will be done, according to the way it is exactly supposed to be done when a new vaccine or drug is developed. There will be no corners cut. The only way that we will accelerate this is by these overlapping phases – by overlapping phase I and II, II and III; and preparing ahead for regulatory harmonization, licensing and preparing ahead for manufacturing. Preparing ahead for the policy and the delivery. So, you can do all that planning in advance to cut that time, but not cut the time for the trial, that is needed to establish the safety of the vaccine. 

Q8. Can a vaccine stimulate an immune response that will give protection?

The simple answer is that we are learning about immunity on a daily basis. What is encouraging is that, most people who recover from COVID-19 develop neutralizing antibodies, the vast majority of them. This means that a vaccine has a good chance of eliciting protective immunity, also by generating neutralizing antibodies. The vaccines that are being tested so far, have also shown that they stimulate the cellular immune response. 

We have two main types of immune response – what we call the cellular immunity which are the T-cells, what we call humoral immunity which are antibodies produced by B-cells. Normally when the body sees particular type of bacteria or a virus, it could stimulate one or both these arms of the immune system. In this case, it seems to be stimulating both. Both the T-cells and the B-cells, initially of course, come out and react against the virus or the bacteria. They are supposed to kill this pathogen which has come into the body and get rid of it. But then having seen this virus, they also develop a memory of this virus, its proteins. So, these memory cells, they live in the bone marrow for a long, long time.  So, what should happen normally is that when you get exposed again, to the same virus, then these memory cells come out of hiding and are able to get activated and start producing antibodies and the T-cell response. 

There are some diseases for which you can develop long-lasting immunity – measles is a good example. If you have had a measles immunization as a child, you are more or less protected throughout your life. In this case, influenza is different. Because the virus mutates and you need a new formulation of a vaccine every year to re-stimulate the immune system. This is a virus [SARS-CoV-2], it does mutate. It has not mutated to an extent, where we think it will be a problem with the vaccine, but we need the follow up studies to be confident. At this point, we are only six months into this pandemic, we are following people, over a period of time, who have had the infection to see how long these antibodies last. There have been reports that antibodies have a half-life of only 75 days, but that does not mean that those people are not protected, because of the memory that is retained. For other coronaviruses, such as MERS and SARS, the antibodies can last a couple of years. In this particular case, SARS-CoV-2, we need to wait and see. 

IMAGE CREDIT from Pexels: Karolina Grabowska, Poland

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