Prof Salim Abdool Karim Weekly COVID-19 UPDATES

10 March 2022

The 4th wave in South Africa has continued its downward trajectory (slide 1).  You may recall the concerns about how long the recent increase in cases due to BA.2 would last. BA.2 continues to decrease – ie. S-gene target failure has stopped decreasing (Remember that BA.1 has S-gene target failure but that BA.2 does not have S-gene target failure). So, overall omicron cases continue to decline and the small spike in BA.2 cases in children a few weeks ago was short-lived.

So, the question now is whether South Africa will get a 5th wave and when? The answer in short is that no-one knows for sure. But there are clues in the epidemiology of SARS-CoV-2 in South Africa that enable an educated guess. It is nothing more than simple high-school maths (no complex mathematical modelling) that shows that the inter-wave period in SA was consistently around the 3 month mark. Using this observation, we can calculate 3 months after the end of the last wave – this gives us an estimate of 8 May for the start of the 5th wave, if it occurs (Slide 5). In other words, if past trends continue, we can expect the 5th wave to start on 8 May. It will have to be due to a substantially different variant as Omicron infection generates effective immunity against itself and against Delta.

So, just what will this next variant look like. Again, no-one knows for sure. But we have several clues to what characteristics it may need to have to have any chance of displacing omicron:

  1. The primary requirement is transmissibility - the ability to spread faster. This will lead to a higher peak in the 5th wave but a shorter-lasting wave, ie. cases will increase more rapidly and saturate the susceptible population faster.
  2. Being able to spread faster will likely require some combination of a higher viral load, a lower minimum infectious dose, a longer duration of infectiousness or a longer period asymptomatic / pre-symptomatic infectiousness. While the evidence is still preliminary, omicron has been able to achieve some of these characteristics – so, it is quite likely that the Pi (the next letter in the Greek alphabet after Omicron is Pi), should be able to acquire the mutations that can confer these advantages.
  3. Being able to spread faster in a population with high levels of immunity – both vaccine-induced and natural – means that Pi will almost certainly have to have immune escape. Beta, Gamma, Delta and Omicron have been able to readily escape immunity, especially when antibodies have waned to a level that is below the threshold for protection. If the next variant is not able to escape immunity, then it would have little prospect of spreading rapidly and displacing omicron and becoming Pi.
  4. A variant with immune escape but not higher transmissibility is not likely to succeed in becoming Pi. Mathematical modelling indicates that transmissibility is essential (Slide 6).
  5. While increased transmissibility and increased immune escape are essential characteristics required to become the next variant, it is an open question as to whether the next variant will be more or less severe than omicron. Delta, which produced quite severe disease was able to become globally dominant in the midst of quite high background immunity – so, there is no need for the next variant to be less severe in order to become Pi. We need to avoid our fervent hope and wish that Pi is more like omicron to actually believing that it can only be like omicron. Pi could just as easily be severe or mild, even in the presence of background immunity – this is one issue where we have few clues to make an educated guess.

There are several lines of investigation underway to make a vaccine that is less susceptible to the vagaries of the variants – I can recommend the article in Nature that is on slide 6 if you are interested in whether we are likely to get a variant-proof vaccine anytime soon.

As the challenge of Long Covid grows, the latest issue of Nature had this finding (Slide 9), which took me aback – those individuals who had Covid have reduced brain size! Yes, you read correctly – Covid-19 makes the brain smaller! And the difference is more than minimal. The graph at the bottom on slide 9 shows how the ratio of brain to intracranial volume has been changing in those who got Covid-19. It is not yet clear if this is reversible. Just one more reason why we need to continue to reduce the risk of viral transmission and not just throw in the towel (as we are seeing in several countries) to let the virus spread unimpeded.

Finally, there have been several studies in the last 2-3 weeks providing more evidence to show that vaccines reduce the secondary attack rate. I remember how a scientist in South Africa proclaimed that the country had reached herd immunity when the first wave ebbed, claiming that, “The only plausible way to explain this decline, Professor xxx told Sky News, is that some sort of herd immunity has been reached..” only to later proclaim that herd immunity is not possible because vaccines prevent severe disease and not infection. Both statements or positions on herd immunity are data-free opinions. The evidence is now steadily accumulating that vaccines do reduce the secondary attack rate – which is essential in order for vaccines to provide a population level benefit to those who have not been vaccinated or those where vaccine immunity is not sufficiently protective. Since steadily improving vaccine coverage increases population benefit by reducing overall transmission (Milman, Nature Medicine – slide 13), it is important to continue efforts to reach higher levels of vaccine coverage – it is more appropriate to think of herd protection as progressively increasing benefit rather than all or nothing.  I had previously shared the compelling NEJM paper that showed a 68% reduction in the secondary attack rate following 2 doses of Pfizer (Slide 11).

A new paper just out in Science, provides yet more good evidence of population benefit – through an ingenious study design. They took families with children ineligible for vaccination and looked at the infection rates in these children depending on whether none, one or both parents were vaccinated. The results are well illustrated in the diagram on slide 12:

  1. Children with one vaccinated parent were 26% less likely and children with two fully vaccinated parents were 72% less likely to get infected compared with children with neither parent vaccinated. A 72% reduction in the secondary attack rate is impressive!
  2. But it gets better! Children with two boosted parents were 58% less likely to get infected than children with double-vaccinated parents.
  3. This population level benefit was observed in both the alpha and delta waves - 94.4% fewer infections in 2x vaccinated parents in the Alpha wave and 86.3% fewer infections in 3x vaccinated parents in the Delta wave.

There is also another paper in Science by Prunas that differed with lower protection that in her preprint that I included on slide 13. And just a reminder that the NEJM paper shows an association between viral load and the secondary attack rate. I had made these points before, but just to remind you that vaccines seem to reduce the risk of transmission from a vaccinated person through reducing infectiousness – both amounts of virus in the nose (slide 14) and the duration of infectiousness (slide 15).

Just with the Eyre study (NEJM) and the Hayek study (Science), there is good evidence that vaccines benefit not only the vaccinee but the population including the unvaccinated, as seen in the vaccine-ineligible children. It is important to note that many elderly people are not well protected by vaccines due to their lower immune response and so will depend on this additional population benefit to reduce their risk of infection. This makes an even stronger case for people in congregate settings, eg. universities, offices, etc to be vaccinated – not just for their own benefit but to help protect others as well. While it may be acceptable for a non-vaccinated person to say that (s)he does not want the self-benefit of vaccines in reducing severe disease, but it is not acceptable for non-vaccinated person to put elderly people at risk of severe disease – we will need the population prevention benefits of vaccinations (the protection that vaccinated people give the most vulnerable in our community) as we prepare for the 5th wave.

Salim S. Abdool Karim, FRS
Director: CAPRISA
CAPRISA Professor of Global Health: Columbia University