Covid-19 vaccine expert Prof Madhi on trial delay, township immunity – and why lockdown is a bad idea

In this interview with BizNews editor Jackie Cameron, Professor Shabir Madhi – a vaccinology expert of global standing – says this country is going suffer because of the economic repercussions of Covid-19, rather than Covid-19 related deaths and severe disease. He says he expects the virus to linger, but there are other ways of trying to curb its spread. Like Discovery Health’s CEO Ryan Noach, Professor Madhi says he believes South Africa’s death rate from Covid-19 is far higher than government statistics suggest. He also shares his thoughts  on the recent halt in the AstraZeneca Covid-19 vaccine trials and what that means for other vaccine trials and whether South Africans in townships are relatively immune to the coronavirus. – Jarryd Neves

Professor Madhi, you are one of South Africa’s experts on the vaccine trials. We’ve had this news that AstraZeneca has put its phase three on hold. What does this actually mean for the South African trials?

The South African study is actually being overseen by the same data and safety monitoring committee that’s overseeing the study in the United Kingdom and Brazil. As you are aware, there was a medical event that was reported from one of the study participants in the UK, which is currently undergoing a review by the Independent Data and Safety Monitoring Committee (DSMB).

Whilst the Data and Safety Monitoring Committee are undertaking this review, they’ve requested all of the sites to postpone further vaccination. So the South African site is similarly affected – as are the sites in the United Kingdom and Brazil – in that we have postponed vaccination until there’s adequate interrogation of the medical event that has been reported. 

Do we know what actually happened? Was this the Covid-19 vaccine or was it the placebo?

We certainly don’t know. I think what’s important to emphasise is that this is not unique to the Covid-19 vaccine. This is part of the discourse of the clinical evaluation of any intervention – especially in the early stages of its development – in that we are extremely cautious in terms of reviewing things that might be associated with vaccination, irrespective of whether the participant received the vaccine or not. The participants – as well as investigators – are usually blinded in terms of whether the participants received the vaccine or a controlled substance, which in the United Kingdom happens to be the meningococcal vaccine. 

So in any of the studies – the phase one/phase two studies especially – where much of what happens with the vaccine is unknown, this sort of event could raise a flag in terms of needing further interrogation, to exclude that the medical event is actually related in any way to vaccination. It’s not unique to Covid-19 vaccines. This would be part of the discourse of any phase one/phase two study, where any intervention is being investigated – both for safety as well as in terms of its efficacy.

How does this affect the other trials that are currently underway in South Africa? 

It doesn’t have any bearing on the other vaccine trial that is underway because that is a completely different construct. That is the subunit protein vaccine, which is developed by another company. That study – as well as many other Covid-19 vaccine trials which are not using the vaccine that is now licensed to AstraZeneca – are still very much ongoing. If in any of those studies, a similar event or any other sort of event which is possibly associated with the vaccination and is deemed to be extremely serious, those studies would also be affected. The independent Data and Safety Monitoring Committees of those studies would probably respond in a very similar fashion as the DSMB has for this particular study.

We are going at quite a rapid pace compared to the usual pace for vaccines. Is that right? 

That’s correct. So we are trying to achieve what is usually achieved in a 10 and a half year period (on average), we are trying to achieve that probably in a 10 and a half month period. So we certainly are very much on an accelerated pathway in terms of doing the clinical evaluation of the Covid-19 vaccines.

I think this is an example which shows that we’re not taking any shortcuts. If there are any concerns that are being raised, they’re actually being addressed timeously and not at the expense of the safety of participants. So these built-in mechanisms to ensure the safety of the participants is essential. If anything, this particular event highlights the intense scrutiny under which the studies are being taken with the safety of participants of paramount concern, both to the data and safety monitoring committee, the investigators as well as on the part of AstraZeneca. 

Covid-19 vaccine: Russia, world progress

Where is the world now, in terms of getting to a vaccine? We heard a while ago that Russia had approved one. Realistically, how close are we to getting a vaccine to help protect everybody from Covid-19? 

I think this particular example illustrates why you can’t put too much emphasis on the Russians having a licensed vaccine, based on the limited investigation of the vaccine for immune response. This is the equivalent of what is known as a phase one study. You only need to do larger studies, into thousands of individuals to be able to pick up these sort of safety concerns. It would be premature to say that the Russians have got a licensed vaccine, because that vaccine certainly needs to undergo further scientific interrogation before we can be assured of its safety. There isn’t any evidence to actually show that it protects against Covid-19.

Currently there are a number of studies, up to 40 different studies that are in human trials. About seven of them are in phase three studies. In many of these phase three studies, about three or four of them are already under way in the US. These are studies that are enrolling up to 30,000 participants. That is to assess for safety as well as for efficacy (whether the vaccine protects against Covid-19). In terms of the timelines, as to when we will know the answers from these studies, is largely dependent to some extent on the speed at which we complete the enrolment of this large number of participants, but also in terms of the amount of virus that is circulating.

Read also: AstraZeneca Oxford Covid-19 vaccine trials paused after participant gets sick

The way these studies work, is that eventually you need to get a certain number of people that actually develop Covid-19, for you to be able to do an analysis to determine whether the vaccine protects against the virus or not. The timeline that it takes to get to those required numbers is completely dependent upon the circulation of the virus in the community. It’s really difficult to predict. The larger your sample size, the sooner you’re likely to get to that particular point where you’ve got an adequate number of cases to do that sort of evaluation. I think most people are still optimistic that we might be able to get an answer, for at least two or three of the vaccines that are currently in phase three. We might be able to get an answer by November or December of this year. 

South Africa has been in the world headlines because we have a very low death rate compared to the rate of infections. You were quoted in a BBC report, saying that there may be some immunity that seems to have developed in South Africa. Could you elaborate on that theory that’s currently becoming quite popular? 

I think there are two parts to that. The first part is whether South Africa does in fact have a low death rate, and the answer to that is no. The way the data is being interpreted is actually quite misleading. When we talk of a low death rate, different people are using different sorts of figures to illustrate what they’re trying to get to. They’re referring to what is known as a case fatality rate, which in South Africa is about 2-2,5%. You can’t use that as a measure to compare it to what happened in the United Kingdom, Italy and France.

When they calculated the case fatality rate, they were calculating it based on the denominator being individuals that were mainly hospitalised cases of Covid-19. In South Africa, our denominator includes mild cases, asymptomatic individuals as well as Covid-19 cases. So it’s fundamentally flawed to make that sort of head to head comparison because the denominator differs and that difference in denominator influences that case fatality rate. 

So when you look at hospitalised cases in South Africa, our case fatality rate is no different compared to the UK, Italy and Spain. It is about 12-14%. I think a misconception that South Africa has had a remarkably low case fatality rate compared to other settings.

In terms of the way to better measure as to exactly how the death rate in South Africa compares to other countries, using the UK as an example, their death rate is roughly about 60 individuals per 100,000 of the population for Covid-19. In South Africa, let’s look at data from the Western Cape, as an example. They’ve probably got the best data of all of the provinces and are probably not under detecting Covid-19 cases. The death rate in the Western Cape – in some of the districts – is in fact higher than in the UK.

In Khayelitsha and Klipspruit, the death rate is above 60 per 100,000. I think it’s a misconception that South Africa has an unusually low death rate. That being said, there is something else at play. So the percentage of the population that seems to have been infected in South Africa, is much lower than the proportion of the population that was estimated to have been infected in the UK, for example. In many settings in the Northern Hemisphere (in the first wave of the outbreak) between 5% and 15% of the population was infected. It obviously varies across the country. In New York for example, it was up to 25% of the population that were infected.

Based on recent South African data from the Western Cape and Gauteng – and these are preliminary results – it indicates that anything between 35 to 45% of individuals in these provinces – especially in urban metros – might have been infected in South Africa. With that high rate of infection, we would expect our death rate to be much higher than in the UK. So we’re not actually seeing the high infections translate into a huge number of severe Covid-19 cases or huge numbers of people that have died from Covid-19 in South Africa. It’s much lower than what people have estimated would have occurred in South Africa with that rate of infection. 

So what’s the reason for this? We’re not completely sure. What I’ve put forward is really a hypothesis and it’s a hypothesis that we need to test. It’s not an absolute finding that this is the reason why this high force of infection hasn’t translated into lots of severe disease.

The hypothesis is – and there’s some data to suggest that this might be the case from high income countries as well – that people (especially those living in very overcrowded settings) are actually much more exposed to common cold coronaviruses, which have been circulating in humans since the 1960s. People develop an immune response against common cold coronaviruses and there is a possibility that that immune response might actually confer some cross protection, at least against the progression of infection of the SARS-CoV-2. 

This basically means that people might still become infected with the virus. However, the clinical course is attenuated because of death and the underlying immune responses that have been induced by the common cold coronaviruses. That might be sort of attenuating the clinical course. There might be other reasons, but this might be one of the possibilities why we haven’t seen the high force of infection that has occurred in South Africa translate into hundreds and thousands of cases of severe disease, as well as tens of thousands of individuals that die from Covid-19.

Early on in the pandemic, we heard that the TB BCG vaccine was being explored as a possible way to protect against Covid-19. What are your thoughts on BCG now, having reduced maybe the risks for South Africans? 

I think that was based on empirical evidence. There wasn’t really any hard science behind those sort of initial hypotheses. Recently there was a study in Switzerland, which basically indicates that there isn’t any benefit in terms of infant BCG vaccination in protecting against Covid-19. That is a study that was done in Switzerland. They’ve got a very unique population in the sense that there were some people that did receive BCG during infancy and others that didn’t.

In a country like South Africa – where the majority of individuals are vaccinated with BCG – it becomes difficult to do that sort of an analysis. I think most of the evidence points in the direction that BCG vaccination probably is not conferring immunity against developing Covid-19. There is another study that’s currently underway in South Africa looking at BCG revaccination to see whether that protects against Covid-19. Those results are not yet available.

Read also: How world sees SA: Township clues to low coronavirus death rate – BBC

In terms of infant vaccination, I think those early suggestions were made at the time when the virus hadn’t really spread to Southern Hemisphere countries, where BCG is more commonly used. They were using evidence which probably didn’t stand up to scientific scrutiny or scientific rigour in terms of its interpretation.

South Africa reported a huge drop in GDP this week of about 50% linked to the Covid-19 shutdowns. Do you think if we have another wave, we should go the shutdown route again to save lives?

Absolutely not. There’s absolutely no reason why South Africa should go into another highly restrictive level of shutdown. In fact, we probably should be at level 1 right now. I’ve said before that even when we were at level 5, there was no reason to actually extend it beyond the initial three weeks, let alone continuing with high levels of restriction. The levels of lockdown probably just served one purpose eventually, which was to allow healthcare facilities to better equip and prepare themselves for what was going to be a surge of Covid-19 cases.

But it did very little in terms of the total number of people that have been infected in South Africa. There’s no reason why South Africa needs to go back into a lockdown. It really depends on what you’re trying to achieve with a lockdown. Right now we are in a space where we’re not going to achieve much by going into a higher level of lockdown.

That doesn’t mean we need to be an open society and allow for mass gatherings. There are some restrictions that still need to be kept in place, probably up to the end of next year. We need to be more measured in terms of our response, so that we actually avoid further negatively impacting the livelihoods of people as well as the economy of this country. This country is going to be crippled due to the economic repercussions of Covid-19, rather than Covid-19 related deaths and severe disease.

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