Prof Salim Abdool Karim Weekly COVID-19 UPDATES

7 April 2022
Today, the missive will be covering 3 issues:
1. Globally, the pandemic is following the expected downward trajectory (Slide 6), despite the rise of cases in China. The trajectory at global level that I am expecting is based on what we saw in South Africa following a blip caused by BA.2. Since South Africa was first to experience the omicron wave, it provides a glimpse of what is to come weeks to months later globally and in many other countries.
2. South Africa is currently in the trough between waves but there are some early signs that need to be monitored – the Ro is rising (Slide 8) (which is expected even with a few additional cases when the base number of cases is low and so should not be over-interpreted) and the test positivity rate has stopped declining. This is not yet an indication of a possible new wave but these were early indicators (Slide 9) when past waves started. With these 2 indicators, it could just be background variability or another small blip by an omicron sub-variant. Before we can make any conclusions, we need to watch the trends over the next few weeks in this space!
3. New omicron sub-variants and recombinants are being reported on a regular basis. So, what should we make of BA.2, BA.4, XE, Deltacron and other viruses that are being reported? (Slide 10) It is not often appreciated that there were more than 150 different minor variations of the Delta variant when we was spreading across the world. But now with omicron, we have much more sequencing and so many more sub-variants are being identified. These variations in omicron occur through 3 separate mechanisms:
a. Since SARS-CoV-2 generates a few mutations as it routinely spreads (as all viruses do), we must expect minor variations with mutations that have little/no significance. These minor mutations are listed separately on the phylogenetic tree as sub-variants but they usually have no clinical or public health implications.
b. When a new variant emerges, it can initially have a few different sub-variants that proliferate as the new variant takes hold and with time, a dominant sub-variant will usually push the others aside. In the case of omicron, there were at least 3 sub-variants when it emerged but BA.1 quickly became dominant. When the initial SARS-CoV-2 (referred to novel Coronavirus at the time) was reported in Wuhan, there were actually 2 different sub-lineages spreading in December 2019 – so multiple initial lineages have been reported right from the original ancestral strain.
c. New sub-variants can also be created by recombination. For example, BA.4 was created by a recombination of BA.1 and BA.3. These recombinations (partial nucleic acid fragments from 2 or more different sub-variants join together to create a new sub-variant). These recombinations are common in Coronaviruses and occur commonly in bats as well. There is a hypothesis that SARS-CoV-2 was created through recombination in bats without a secondary host (such as pangolins, that had previously been suggested as an intermediate host). Recombination is common in nature – not just in viruses. Bacteria, for example, can become antibiotic resistant through gene recombination – sometimes referred to as jumping genes. This is quite common in gut bacteria.
So, will one of these sub-variants or recombinants become Pi – the next variant of concern, if WHO names it after the next Greek alphabet letter? The rate at which the media hypes up each new sub-variant, you would be forgiven for thinking that the next variant of concern is here. As new sub-variants and recombinants emerge, they are sometimes given dramatic names like “DeltaCron” or “Omicron XE”. These names conjure images that hype the actual nature of the newly emerging viruses. I give some of our scientist colleagues some leeway for giving new sub-variants exciting names – it is just their attempt to get some attention paid to their variant reports. Once you look beyond the hype, the picture is clearer. Sub-variants usually have too few mutations to be materially different from the immunogenic structure of the other sub-variants and so has little prospect of becoming dominant as immune responses, especially antibodies against the dominant sub-variant will usually confer immunity to the other sub-variants with minor mutations, even if they are more transmissible.
For example, infection with omicron (most commonly BA.1) in a vaccinated person with no past infection generates good immunity to all the variants of concern (Slide 11 – Rossler in NEJM - note that this immunity will wane over time). Since omicron has been spreading so fast and so widely compared to past variants of concern (Slide 7) across the world, there are many vaccinated people who became infected with omicron and who now have good immunity to all the existing variants of concern. Similar immunity is evident in unvaccinated people or people with past infection. Since infection with omicron generates such good immunity to existing variants of concern, it will be very difficult for past variants like Beta or Delta to come back and cause a new wave – the next wave has to be caused by a new variant, with limited antigenic similarity to omicron or will need to emerge only when omicron-generated immunity has waned sufficiently (we do not know how long this will be). 
Further, no other variant of concern emerged as a recombination or sub-variant of past variants. While this could be different now, it is unlikely that this will change. So, if Pi does come to exist, it will have to be antigenically distinct ie. through an independent evolutionary lineage. This will enable it to escape existing immunity (from past infection or vaccination). But escaping immunity on its own is not going to be enough, the future variant Pi, will also need to spread faster (based on the modelling article in last week’s missive). But omicron spreads so fast – is it realistic to expect a new variant to spread even faster. Yes, omicron XE has already demonstrated that it is feasible to spread faster than omicron BA.1. XE is estimated to be quite a bit faster spreading than the other omicron sub-variants.
In summary, you can mostly ignore the hype surrounding sub-variants and recombinants as potential causes of the next wave. At this time, there are no publicly available SARS-CoV-2 sequences that look like they will lead to Pi. If Pi does emerge, and there is a reasonable likelihood that it will emerge, it will be really fast-spreading and by the time we identify it, it will likely already be spreading in several countries leading to a new wave of infection.
Salim S. Abdool Karim, FRS
Director: CAPRISA
CAPRISA Professor of Global Health: Columbia University