Rejected vaccine has a role — Madhi
• High-risk categories in local future hotspots could still benefit from taking a chance with discredited vaccine that will expire anyway
The government’s decision to offload the AstraZeneca vaccine instead of using it to protect high-risk individuals from severe Covid-19 is a mistake, leading vaccinologist Prof Shabir A Madhi says.
In an opinion piece written for Business Day, Madhi says the 1-million doses, which cost SA R75m, are likely to save the lives of those at risk in the next wave of infections.
Experts expect a third wave to hit SA in the winter months.
Madhi, who is the dean of the Wits Medical School, says the decision by the government not to use the vaccine leaves older and vulnerable citizens without any potential protection from Covid-19 as it is not likely that enough other vaccines will have arrived in SA by winter.
The decision not to deploy the vaccine in SA goes against the spirit of what was previously espoused by the department of health: that it would take its lead from World Health Organization recommendations, he says.
His study of the vaccine tested in young people in SA showed it does not prevent mild cases of the B.1351 variant, which emerged in SA.
The vaccine also will not stop the virus spreading.
WARNINGS
But Madhi has repeatedly warned that this does not mean the 1-million doses, which will expire at the end of April, should go to waste.
The similarity of the AstraZeneca vaccine to the Johnson & Johnson (J&J) vaccine tested in SA shows there is a “biological plausibility” that it will do just what the J&J vaccine does and stop hospitalisations and death in those most at risk of Covid-19 complications. SA has instead decided that the vaccine should go to AU countries, where the B.1351 variant supposedly is not circulating — something Madhi suggests is unlikely. It is more likely not to have been detected in these countries.
Madhi says that like the AstraZeneca vaccine, most firstgeneration Covid-19 vaccines are unlikely to bring about an interruption in transmission of the virus or lead to herd immunity in places where variants such as B.1351 are circulating.
The past month has been a roller-coaster ride when it comes to the rollout of Covid19 vaccines in SA. The government has halted the distribution inside SA of 1-million doses of the AstraZeneca vaccine and is poised to make a potentially historic mistake.
After much criticism early in January 2021 of the virtual absence of any strategy beyond procuring a limited quantity of Covid-19 vaccines through the Covax facility, the government successfully negotiated procurement of 1.5-million doses of the AstraZeneca Covid-19 vaccine through a bilateral agreement with Serum Institute of India.
This was, however, at a price ($5.25) more than double that negotiated by EU countries ($2.5) to pay for the same vaccine (but from a European manufacturer). Within a week surrounding the fanfare of the arrival of 1-million doses of the AstraZeneca vaccine at a cost of R75m came the disappointing news from a study evaluating this vaccine in SA since June 2020 that the vaccine does not protect against mainly mild Covid-19 (usually limited to infection of the upper airways).
The telltale signs that the AstraZeneca (and probably all other) Covid-19 vaccines might be less efficacious in protecting against mild-moderate Covid-19 in SA was evident from reports that have emerged since midJanuary 2021, from local scientists, which indicated that the ability of antibody induced by natural infection by the ancestry SARS-CoV-2 variant had greatly diminished activity against the B. 1.351 variant that emerged in SA late in October 2020.
This was a consequence of gene mutations that affected key epitopes of the spike-protein of the virus, which are the components of the protein against which most of the current first generation Covid19 vaccines induce functional antibody. Consequently, it was expected that even antibody induced by the first-generation Covid-19 vaccines would have diminished activity against the B. 1.351 variant, which had undergone substantive changes in key components of target of these vaccines.
Corroborating this were interim results from another study, also conducted in SA, on the Novavax Covid-19 vaccine. This drew much less publicity than the results of the AstraZeneca vaccine study, despite it being the only vaccine then to show protection against the B. 1351 variant.
Notably in the Novavax study, the attack rate of mildmoderate Covid-19 (probably mainly due to the B. 1351 variant) did not differ in the unvaccinated control group between those who had already been infected with the SARSCoV-2 prototype virus compared to uninfected individuals at the time of studyenrolment.
This provided the first conclusive evidence that the mutations included in the
B. 1.351 were clinically significant, and that despite 35%-45% of South Africans (especially in densely populated urban areas) likely to have been infected during the course of the first wave by the prototype virus, such infection did not confer any protection against developing mild to moderate Covid-19 due to the B. 1351 variant.
The rude awakening of these results (for some) was that the notion of relying on “herd immunity” evolving by allowing people to be unabatedly naturally infected was doomed not to materialise.
Instead, the high force of infection that occurred in SA (despite attempts at restrictive and economically devastating lockdowns) probably contributed to the problem of the evolution of a variant that was now resistant to antibody induced by past infection.
Furthermore, the Novavax vaccine results from the SA study showed lower efficacy (49%-60%) against mainly mildmoderate Covid-19 mainly due to the B. 1.351 variant compared with results of the same vaccine in the UK (89% efficacy), where the efficacy was not affected by another variant (B. 1.1.7) circulating there.
In studies on other Covid-19 vaccines, including the mRNA vaccines of Biontech/Pfizer and Moderna, for which vaccine efficacy has been reported to be 95% against Covid-19 due to the ancestry virus, laboratory investigations have reported 6.5-8.5 fold reduction in the potency of the antibody induced by those vaccine against the B. 1351 variant relative to that observed for the prototype virus.
For the Johnson and Johnson (J&J) vaccine, which uses a similar technology for design of vaccine as the AstraZeneca vaccine and also induces almost identical functional antibody response after a single and twodose schedule, the laboratory testing of the antibody activity against the B. 1351 variant have not yet been released. I expect they will be no different to that observed for the AstraZeneca vaccine.
In contrast to the lack of efficacy of the AstraZeneca vaccine against mild-moderate Covid-19 in SA, the J&J Covid-19 vaccine results from the SA arm of the study reported a 89% reduced risk of severe Covid-19, also mainly due to the B. 1.351.
Unlike the AstraZeneca vaccine trial in SA, which targeted a younger age group demographic with low prevalence of comorbidities, a high proportion of participants in the J&J study were individuals at high risk of severe disease that is, older than 60 and with high prevalence of comorbidities such as diabetes and hypertension.
Hence, any direct comparison of the efficacy of these two vaccines is misguided and fundamentally flawed. Whether the J&J vaccine indeed protects against the same spectrum of mild illness that is caused by the B. 1.351 variant is yet to be reported or established for any such head-to-head comparison between these two vaccines (or other Covid-19 vaccines) to be meaningful.
So why might there be a difference in how well Covid-19 vaccines work against mild illness compared to severe disease? First, this would not be unique to Covid-19 vaccines. Vaccine against other respiratory pathogens, including seasonal influenza virus, respiratory syncytial virus in infants born to vaccinated women, and pneumococcus consistently report that protection against mild illness (usually of the upper airways) is more challenging to accomplish than prevention of severe disease (usually lower airway disease — for example, pneumonia).
The reasons for this may differ between vaccines, including possibly requiring lower concentrations of antibody to protect against severe than against mild illness. In addition for Covid-19, challenge studies in vaccinated nonhuman primates indicate that protection against lower airway infection can be conferred largely independent of vaccine induced antibody, through the stimulation of natural killer cells (also referred to as part of T-cell immunity).
Fortunately, there is a broader repertoire of spikeprotein peptides that induce Tcell immunity, most of which are unaffected by even the B. 1.351 spike protein mutations. For the AstraZeneca vaccine, almost none of the B. 1351 mutations are likely to compromise the killer cell responses induced by the vaccine.
Consequently, there remains a strong biologically plausible reason to expect the AstraZeneca vaccine will protect against severe disease due to the B. 1351 variant, likely to a similar magnitude as the J&J vaccine.
It is largely premised on this that the World Health Organization in mid-February 2021 recommended that the AstraZeneca vaccine still be rolled out even in countries where the B. 1.351 variant or other similar variants of concern are circulating.
The AstraZeneca vaccine, as well as many other firstgeneration Covid-19 vaccines, are unlikely to bring about interruption in transmission of SARS-CoV-2 or protect against mild infection where these variants of concern such as the B. 1351 variant are circulating.
This would be compounded if there is sluggish rollout of the vaccine — drawn out over a year, rather than within a few months. Nevertheless, these first-generation Covid-19 vaccines even in settings such as SA still provide the only sustainable option of preventing flooding of our hospitals with severe Covid-19 cases and mitigate Covid-19 deaths once the next resurgence is upon us.
Hence, the decision by SA not to deploy the vaccine goes against the spirit of what was previously espoused by the department of health — that it would take its lead from WHO recommendations.
Furthermore, this decision inadvertently leads itself to choosing between leaving highrisk individuals largely unprotected against being hospitalised and dying of Covid19, as opposed to rolling out the available AstraZeneca vaccine to those who choose to take the chance of deriving potential protection by being immunised with a safe vaccine that has been established to reduce the risk of severe Covid-19 by 80% even among people older than 80 years in the UK.
The decision by SA would have less repercussion if highrisk individuals were likely to be vaccinated with other Covid-19 vaccines for which clinical (and not only extrapolation of laboratory-based data) protection is established against the B. 1351 variant before the next resurgence.
Unfortunately, based on the latest sharing of information on the pipeline of Covid-19 vaccines likely to become available to SA, other Covid-19 vaccines, all besides the J&J vaccine which will not have been evaluated clinically against the B. 1351 variant, are only likely to become available from midApril onwards, without any clear indication on what quantities and how soon these may be deployed into the arms of people.
Consequently, the current strategy to try to offload the AstraZeneca vaccine to other African countries where the variant might not have been identified (mostly due to there being little sequencing to actually identify its presence rather than its actual absence) is problematic. This is compounded by the current expiry date of the vaccine being April 30 2021.
Even were there to be reversal of the decision by government to take its chances with the AstraZeneca vaccine and target it to high-risk individuals who choose to take their chances of being vaccinated rather than remain unprotected when the resurgence is upon us, getting a million people vaccinated before the end of April would be a mission.
Every additional day of procrastination lends itself to much of the R75m used to procure the vaccine going to waste, while the elderly and other high-risk individuals would certainly remain unprotected as opposed to being offered a fighting chance of being protected against Covid-19 severe disease and death.
PROCUREMENT WAS AT A PRICE ($5.25) MORE THAN DOUBLE THAT NEGOTIATED BY EU COUNTRIES ($2.50) FOR THE SAME VACCINE
EVERY DAY OF PROCRASTINATION LENDS ITSELF TO MUCH OF THE R75M USED TO PROCURE THE VACCINE GOING TO WASTE
● Madhi is the dean of the Faculty of Health Sciences at the University of the Witwatersrand and director of the SA Medical Research Council Vaccines and Infectious Diseases Analytics Research Unit.
● Declaration of interests: National principal investigator of the University of Oxford (AstraZeneca vaccine) and Novavax Covid-19 vaccine trials. The AstraZeneca vaccine study was funded by BMGF and SAMRC, and the Novavax vaccine trail; by BMGF and Novavax. All funding for these studies goes to the Wits Health Consortium of the University of the Witwatersrand.