University of the Witwatersrand’s Professor Shabir Madhi, the lead investigator in Novavax vaccine trial, revealed during a late-night press conference on Thursday that their data showed there was a high risk for patients who had been infected by the “original” coronavirus infection to be reinfected by the mutated South African variant (aka B1.135).

After weeks of uncertainty and speculation, during a press conference just before midnight on Thursday 28 January, the lead investigator in the Novavax vaccine trial and dean of Wits University’s Faculty of Health Sciences, Prof. Shabir Madhi announced that their vaccine is the first that has shown high levels of efficacy against the B1.135 variant which causes more than 90% of all COVID-19 infections in the country, and among the study participants. Similarly, the vaccine efficacy in the UK showed high efficacy in a setting where approximately 50% of the cases were due to another variant circulating in the UK that is more transmissible than earlier prototype SARS-CoV-2 virus. 

Describing the result of 60% protection (reduced risk) against the B1.135 as something he did not dream they would obtain, Madhi recounted their quest to find a vaccine effective against the South African mutation of the virus – one that mutated to make it even more contagious and resistant to immunity that has been induced by past infection, as well as concerning laboratory experiments on other vaccines such as the mRNA vaccines that demonstrate 6-8.5 fold impaired functionality of the induced antibody against the B1.135 variant. .

“Sixty percent was something I did not dream of when we saw how poorly natural immunity induced by infection with prototype virus fared against the B1.135 variant. It might sound disappointing but it is …also about immunization coverage.  We must also look at the public health impact,” he said.

He said Novavax now plans to create a vaccine that will include epitopes from the “prototype” virus and the B1.135 varaint within the next few months. 

“At the moment it is the only vaccine showing objective efficacy against the South African variant,” he said.  

Madhi has previously explained that the Novavax vaccine uses “a more tried-and-tested approach”  taking the [spike] protein of a coronavirus and injecting that into the individual, causing an immune response that will destroy the virus.

“Nothing comes as a surprise anymore. SARS-COV-2 has taught us to be humble and never second-guess the virus,” he said.

Madhi is also the executive director of the Vaccines and Infectious Diseases Analytics Research Unit at Wits.

“The South African data also emphasise the importance of conducting vaccine trials in South Africa, so that we can evaluate the efficacy of vaccines in the local context. The data have significant public health implications, particularly because they are the first to report the efficacy of a Covid-19 vaccine against the [South African] N501Y.V2 variant and demonstrate the real risk of reinfection in those previously infected with prototype virus ,” says Madhi. “I am encouraged to see that Novavax plans to immediately begin clinical development on a vaccine specifically inclusive of targeting the variant dominating in South Africa.”

The two variants of the virus were identified in December 2020, but have possibly been circulating since October 2020. In the case of South Africa, scientists found that the rapidly emerging strain, known as 501Y.V2, was more contagious and spread faster through communities. The strain was first identified in Nelson Mandela Bay after doctors raised the alarm that they were seeing significant shifts and changes in infection patterns in the metro.

South Africa has 122,496 active cases of coronavirus infections, according to the latest statistics released by the Department of Health. Since the start of the pandemic in South Africa more than 43,000 people have died of Covid-19, with the South African excess mortality from natural causes modelling indicating that the actual number of COVID-19 deaths has already passed 100,000.

Providing his impressions of the state of the pandemic in South Africa Madhi said after the first wave of infections started plateauing the daily number of infections was still around 2000. 

“We still had a significant amount of community transmission taking place. In November we saw a resurgence in the Eastern Cape, then in the Western Cape and now across the country. The magnitude of this resurgence caught everyone by surprise.”

He said data from ante-natal and HIV clinics in the Cape Metro showed that 35% to 45% of people had been infected with the virus while preliminary data from Gauteng also shows that as many as 25% of adults in Gauteng were infected. “Data that will be released in the next few weeks show that this may  range between 15-40% in different sub-districts,” he said.

Given these high numbers of infections, he said the second wave should have been subdued as community immunity should have been evolving and have existed for at least 9 months. 

“But [we] did not factor in the evolution of the variant that was less susceptible [to the  antibody that had been induced by past infection with the prototype virus],” he said.

Instead, he added the number of cases in the second wave will be double or triple the number of cases in the first wave. “Deaths were no different. These are already more than during the first wave and unfortunately probably close to 100 000 [based on SAMRC excess mortality dat on natural causes],” he said.

He explained that while they tried to understand the drivers of the resurgence of infections, the variant that evolved in the Eastern Cape was identified and soon became the dominant variant of the coronavirus in South Africa and is now responsible for 90% of infections.

“None of the vaccines were designed against this variant. The South African variant has subsequently been shown to have travelled across the world,” Madhi said, indicating that they received the first news of the variant being identified in two cases in the United States on Thursday night as well. 

“The patients had no history of travel and that means that right now community transmission of the N510Y.V2 variant is taking place in the United States. This has tremendous implications,” he said.

Maddi explained that there currently were two other concerning variants that have been identified globally. One in the United Kingdom and another in Brazil, the latter being as worrisome as the N510Y.V2 variant

“The important message is that all of them share one common mutation making it more than 50% more transmissible. He said the larger concern in the cases of the South African and the Brazilian variants were that the mutations were to pasts of the spike protein that are considered to be critical immunodominant components against which the antibody acts to neutralise the activity of the virus.  

– a part of the virus that forms the cornerstone of many vaccines.

While the first batch of the Covishield vaccine lands in South Africa on Monday, several scientists have raised concerns in the past few weeks over the levels of protection that would be offered against the South African mutation of the virus by any of the Covishield, Moderna or Pfizer vaccines already in use in other countries.

The results released on Thursday night showed that in the South African Phase 2b clinical trial, the Novavax vaccine showed 60% efficacy for the prevention of mild, moderate and severe Covid-19 disease in the 94% of the study population that was HIV-negative. The trial also achieved its primary efficacy endpoint in the overall trial population, including a  limited number of HIV positive and HIV negative subjects combined, showing efficacy of 49.4%.

In a presentation this week, Anban Pillay, Deputy Director-General of the Department of Health, provided a review of the available vaccines, all developed using the non-mutated virus.

According to his review, the Covishield (AstraZeneca/Oxford) vaccine has shown a 60% to 90% efficacy in different trials, the Pfizer vaccine showed a 95% efficacy and the Moderna vaccine 94.5%.

“The higher efficacy of the vaccine in the UK than in South Africa is because the variants circulating in SA are less sensitive to vaccine-induced immune responses by vaccines that were designed to target the prototype virus . Nevertheless, the 60% reduced risk against Covid-19 illness in vaccinated individuals in South Africans underscores the value of this vaccine to prevent illness from the highly worrisome variant currently circulating in South Africa, and which is spreading globally. This is the only Covid-19 vaccine for which we now have objective evidence that it protects against the variant dominating in South Africa,” Madhi said. 

Mahdi is also the principal investigator for the South African trial for the Oxford/AstraZeneca vaccine, known as the Covidshield. He said they will share results next week. Professor Glenda Gray, the president of the Medical Research Council of South Africa and principal investigator in the Johnson & Johnson vaccine trial said they too will release their results in the upcoming week.

Recounting how the Novavax trial came to South Africa, Madhi said they first got a “lukewarm reception.”

“Their plans were to start studies in the United Kingdom and the US. They did not come knocking and banging on our door. They saw very little value of doing the study in South Africa,” he said. “Eventually we managed to convince them.”

He said once the vaccine proceeds to a stage where it will be manufactured, the country might be able to also source it from the Serum Institute in South Africa. 

“We were somewhat over the moon with high efficacy of the Pfizer vaccine,” Madhi said, explaining that for a vaccine to have public health value and to clear the bar for emergency authorisation from health regulators  a vaccine should have an efficacy of more than 50% that lasts for 6 months. 

“It is not about the efficacy alone. It is also about the percentage of the community that will be vaccinated.”

Gray said an efficacy of 60% was good. “It will have both an individual and a public health benefit,” she said. “Even a 50% reduction is an important outcome as it will prevent hospitalisation and death.”

She added that the efficacy of the other vaccines, based on the non-mutated virus, might be reduced with regards to the South African mutation of the virus.

“The public health value of vaccines extends beyond a simple point estimate. The ability of Covid-19 vaccines to impact the pandemic will depend on the product of its efficacy and how quickly we can scale up coverage of the vaccine eventually,” Mahdi added.

More than 4400 people took part in the South African trial for the Novavax vaccine that started in August 2020. At this time the South African mutation of the virus started circulating.

On Wednesday the Minister of Health Dr Zweli Mkhize paid tribute to people who took part in clinical trials for coronavirus vaccines saying they were heroes “who defied all anxieties.”

Madhi also thanked the investigators saying some of them were also infected with the virus while working on the trial.

Around one-third of the participants already had Covid-19, caused by the non-mutated virus, when they enrolled in the study.

Preliminary data shows that of the 27 people in the trial who got sick 25 had the South African mutation of the virus.

“The provisional results from the trial indicate that past infection with the prototype virus is unlikely to protect against Covid-19 illness due to the [South African]  N501Y.V2 variant,” Madhi said but added that the Novavax vaccine provided “significant protection against the variant.”

Might protect against severe disease, not yet known. The reason for not protecting- the antibody produced by the previous infection can’t neutralise the virus currently in circulation.

More than 15 000 participants enrolled in the UK Novavax Covid-19 vaccine phase 3 trial results. The vaccine efficacy was estimated to be 89.3% where 32 out of 56 cases were caused by the UK strain. “It is a very different virus that is infecting our people in SA right now.

The manufacturing of the vaccine for the South African trial was funded by the Coalition for Epidemic Preparedness Innovations (CEPI) and partially supported by a $15 million grant from the Bill & Melinda Gates Foundation. DM/MC

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