When clinicians at Netcare hospitals in Nelson Mandela Bay noticed a sudden spike in Covid-19 admissions in mid-November, they immediately sounded the alarm with Brazilian-born virus hunter Tulio de Oliveira and his team at the KwaZulu-Natal Research Innovation and Sequencing Platform (Krisp).
The scientists sprang into action, working at breakneck speed to analyse specimens from these patients, along with samples from 50 surrounding clinics. The results were astonishing: almost all the infections were due to a new coronavirus variant, now known as 501Y.V2.
“Normally, when we sample 50 clinics, we get 40 different lineages, so when we found just one we knew something was up,” says De Oliveira, a bioinformatician who heads Krisp and moved to SA 22 years ago.
Genetic sequencing revealed 501Y.V2 had dozens of mutations — a startling finding that challenged the then widely held view that the Sars-CoV-2 virus was relatively stable — and set off a global hunt for the evolution of other variants that might explain the sky-rocketing infections in places as far apart as the UK and Brazil. Within weeks, scientists had identified B.1.17 in the UK, and P1 in Brazil, which both shared key mutations with the new variant.
However, genetic sequencing was only part of the job, says De Oliveira. Equally important was the team’s methodical search through the scientific literature to tease out the potential significance of the mutations they identified. The rapid dominance of 501Y.V2 already suggested increased transmissibility, a hypothesis supported by the identification of mutations in the spike protein the virus uses to enter human cells.
Still other mutations pointed to the possibility that 501Y.V2 might be able to evade neutralising antibodies generated by prior infection or vaccines, says De Oliveira.
Independent laboratory experiments led by Alex Sigal at the Africa Health Research Institute (AHRI) and Penny Moore at the National Institute for Communicable Diseases found the new variant does indeed have the capacity to escape antibodies generated by infection with earlier lineages.
Detective work
This kind of painstaking detective work was only possible because De Oliveira is one of a small group of scientists around the world with extensive experience in sequencing novel viruses. He previously worked on Zika, dengue, yellow fever and chikungunya, and had the foresight to set up a genomic surveillance system for Covid-19 in SA well before the first case was reported on March 5 2020.
“We are quite used to responding to viral epidemics with genomics, and started surveillance in February 2020,” he says. It sounds simple, but he moved with lightning speed: the first whole genome sequence of SARS-CoV-2, the virus that causes Covid-19, had only been published on January 11 2020.
By mid-September, scientists had already sequenced 1,365 Sars-CoV-2 genomes from hundreds of clinics across SA, gaining insight into the evolution of a host of new variants. At that stage, they had identified 16 new variants, most with single-letter changes that did not change the function of the virus and were no cause for concern.
They also established that three of these variants — dubbed B.1.1.54, B.1.1.56, and C.1 — accounted for 42% of the infections in SA’s first wave, which peaked in June. By contrast 501Y.V2 swiftly came to dominate transmission, driving a second wave of infections that peaked in early January 2021. In October 2020, 501Y.V2 accounted for just 11% of the samples sequenced by Krisp. By February, that figure spiked to 99%.
Twitter as scientific peer review
All of these advances have been captured on Twitter, the go-to social media platform for scientists, says De Oliveira, who often starts tweeting well before dawn. “What people don’t always realise is that when a pre-print goes public with the community discussing it on Twitter, you are getting hundreds, if not thousands of peer reviews happening within days of your results,” he says. It is a very efficient way to sift the good from the bad, and weak science is quickly exposed.
A pre-print suggesting the coronavirus originated in snakes was retracted within 48 hours after being “completely broken to pieces” by the scientific community, he says.
It takes courage to announce the release of articles on pre-print servers prior to submission to scientific journals, which, traditionally, conduct peer reviews out of the public eye. “Scientists tend to be very polite and factual. They don’t swear at each other, but it can be quite vicious ... a little bit like rugby,” says De Oliveira.
All that scrutiny pays off, however, helping researchers hone their papers, improving their chances of publication by leading journals, such as Science and Nature, he says. By last week, De Oliveira and his collaborators had nine papers on the 501Y.V2 accepted in top journals.
De Oliveira attributes part of the success of Krisp to its close collaboration with two other research groups at the University of KwaZulu-Natal, as both share a building: AHRI, which has pivoted from HIV and tuberculosis (TB) research to pioneering work on 501Y.V2; and the Centre for the Aids Programme of Research in SA, led by health minister Zweli Mkhize’s top coronavirus adviser Salim Abdool Karim.
“We have a very strong synergistic relationship, including genomics, virology and public health interventions. It helps SA be one of the countries leading Sars-CoV-2 science, and quickly translate scientific discovery into public health action,” says De Oliveira.
De Oliveira immediately alerted Karim in early December to the team’s worrying findings on 501Y.V2. Karim then briefed Mkhize about the alarming new developments, prompting a chain of events that saw the government impose new restrictions to slow transmission and reduce the trauma load on hospitals.
Beaches were closed, large gatherings banned, alcohol sales prohibited and the evening curfew brought forward to 9pm. These measures, combined with the “natural restrictions” created by school and university holidays, and the festive season closure of factories, offices and construction sites, helped stem the wave of new infections, says De Oliveira.
“In other countries, people don’t close all the businesses during December and give everyone a collective holiday. If you add it all together we actually had quite a high level of restriction,” he says. Those curbs on social interaction, combined with people’s increasing caution as Covid-19 swept through their personal circles and the natural progression of the virus, meant that by mid-January the worst was over and transmission began to ebb.
Obsessive hand-washing
Krisp has remained notably untouched by Covid-19. Not a single staff member has been infected, despite conducting site visits to hospital outbreaks and processing hundreds of thousands of coronavirus samples. “We take basic infection prevention controls very seriously. We have no meetings in closed spaces, every window in the offices are opened, a lot of our doors open automatically, and we have an absolutely obsessive way of washing our hands 25 times a day. And of course we wear masks,” he says.
De Oliveira is optimistic about the trajectory of the pandemic, despite its devastating health and economic toll. “The scientific advances have been remarkable. There are already so many vaccines with such powerful technology. I honestly think we have the tools to control this virus, both from a public health and vaccine perspective.”
Nevertheless, he worries that people are letting their guard down, setting the stage for a third surge in coronavirus infections in the country. “We have learnt that if we over-compensate for time lost [during restrictions] with parties, going out, and social interactions, the virus will come back. If we could just halt for the next few months, as we scale up vaccination, we may see light at the end of the tunnel,” he says.
Despite the stress of the job, De Oliveira maintains a light touch. The secret he says is meditation, exercise, and a good chuckle.
“It is much easier to go the through the day by laughing and joking, even if we are doing very serious work. And we go for long walks in the Drakensberg, especially in places that don’t have cellphone signal — so journalists don’t disturb you.”
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