Covid 19: Evolutionary interactions between vaccine, immunity and virulence. 

The Covid-19 picture is changing rapidly and if viewed with an unprejudiced mind, keeping several alternative possibilities open, a clear interpretation is emerging. There is a new wave spreading world-wide with unprecedented numbers but at the same time the proportion of hospitalizations and deaths are far less than earlier waves. Why is it so? There are two prevalent explanations which are mutually contradictory. On the one hand this is said to be an epidemic among the unvaccinated; on the other hand the reduced severity of symptoms and lower hospitalization and mortality rates are also credited to the vaccines. Both cannot be simultaneously true, if we do a simple calculation.

Take the case of UK. The ratio of new cases to new deaths has come down from an average of above 10% between April and June 2020 to an average of 0.15 % between December 2021 and today. That is two orders of magnitude. If we have to ascribe the credit for reduced severity to vaccines alone, we will have to assume that in the unvaccinated, the severity remains unchanged. Going by this assumption, and given that 70% of the population of UK is fully vaccinated, for bringing down the mortality by over 50 fold it is necessary that vaccinated people are about 20 times more likely to be infected than unvaccinated people. Since this is absurd, we need to accept that the severity of infection in the unvaccinated has also come down substantially. This can either happen because the unvaccinated have also become immune by natural infection, or because the virus has mostly lost its virulence.

In order to differentiate between these two, we can have a look at Australia which also has about 70 % population vaccinated. But Australia had successfully kept the infection away until recently and therefore the unvaccinated are unlikely to be immunized by natural infection. When the number of cases is small, calculation of death rate is subject to large stochastic fluctuations. So we take only the period in which there were more than 100 deaths per week. This was the situation in Aug-Sept 2020 when the ratio in Australia was over 10 %. Then there was a long time in which there were zero or negligible Covid cases and deaths in Australia. So the population had little chance of acquiring immunity by natural infection. This situation changed again only after October 2021, but now the death proportion was much lower, about 0.6 % and between October 2021 and today it further declined to 0.05 %. Similar to UK if this is to be explained by vaccination alone, we will have to assume that vaccinated people are about 70 times more likely to get infected. Since this is unlikely, it is clear that the reduction in severity and mortality is not explained by vaccination and naturally acquired immunity together. The virus has indeed evolved towards reduced virulence. It was round about 20 times more severe than flu in the beginning which has come down to about 2 to 3 times. It is still more severe than common cold and flu but is moving rapidly to become just another.

Evolution will reduce the virulence of the virus was my clear prediction right from May-June 2020. The literature of evolution of virulence is full of mutually contradicting and confusing arguments. But the case with Covid has been very clear. Multiple studies showed that there was poor correlation between severity of symptoms and viral load. Virulence can give a selective advantage to a virus only if it is tightly correlated to the number of virus particles being shed by the host. If correlation with numbers is poor, there is no selective advantage in being virulent. On the contrary, virulent variants are more likely to face quarantine and thereby restrict their transmission. A milder strain allows the host to move around in the population and thereby spread it more widely. The reduction in severity of symptoms, hospitalization rates and mortality was a conspicuous trait in the beginning. But then it appeared to stagnate and had some hick ups for some time. I was perplexed by this trend but a couple of possible reasons soon became apparent.

There is another, more subtle contributor to selection for lower virulence. The immune status of the host exerts a strong selective pressure on pathogen virulence and this has received little appreciation in virulence literature. Immune response is costly in terms of resource allocation as well as the potential damage to tissues through heightened inflammatory and oxidative components of the process. Therefore it is not wise for the body to launch an all out immune response for every pathogen encountered. At times, particularly for milder pathogens, the cost of the immune response might be greater than the cost of being infected. The host therefore should make a judgment of the invisibility or virulence and accordingly optimize the immune response. The response given to a highly virulent pathogen must be of high intensity, but that given to a milder pathogen should be of minimum necessary intensity. There is some evidence that this is what the body actually does. It gives a high intensity immune response if and when a normal inhabitant turns virulent. For opportunistic pathogens living on the body, exposure to the organism was always there, but what changed was the level of invasion. Even in Covid data, the immune response obtained after a severe infection has been shown to be more intense than an asymptomatic one.

This exerts a differential selective pressure. If the host has a good immune infrastructure and possibly immune memory already existing against the pathogen, a virulent variant will evoke a strong immune response and thereby cause its own destruction. A mild variant on the other hand, may not evoke a strong immune response and thereby may get away causing a mild infection and spreading to a few more individuals. Therefore as the population immunity increases, the pathogen evolves to be milder. This can happen by naturally acquired as well as vaccine induced immunity. Therefore we witness that after a substantial population got vaccinated, the downward trend in virulence got steeper once again.

The concept of optimizing immune response can potentially answer one more question. Why in Covid the vaccine induced immunity appears to be short lived, contrasting with small pox. Corona viruses are seldom that virulent. Most are mild. Pox viruses can be very deadly. It is possible that our systems have evolved to invest less in immunity against Corona viruses and more against poxviruses. This hypothesis is worth exploring further.

But why did the declining virulence appear to stagnate in the middle stages of the pandemic? I think the possible reason is that we blunted natural selection by our own preventive strategies. Selection for milder strain is strong if the severe cases are effectively quarantined and milder ones are allowed to mix in the society. But owing to the contact tracing approach, we tried to quarantine everyone exposed, reducing seriously the selective advantage for the milder varieties. We also reduced our general immunity levels by the extra precautions taken, including masks and sanitizers. There have been reports that in countries where the preventive measures were very successful initially, infections by common endemic and seasonal mild strains of viruses suddenly started needing hospitalization. This is an indication that the preventive measures have actually been creating an immune bankruptcy or what has been called in published literature an immunological debt over time. What can be beneficial in the short run can become counterproductive in the long run. Note that ALL studies showing the beneficial effects of masks are short term studies 3 or at the most 5 months. Nobody has followed the long term effects of regular use of masks. This has never been a part of the mainstream thinking in preventive medicine, but evidence for preventive measures undermining immunity has been published in the context of many different diseases multiple times.

So, the vaccines have been useful in an unexpected way. They don’t seem to have prevented the spread of infection very efficiently. But they appear to have helped in creating a stronger selective pressure for decline in virulence. On the other hand it is quite possible that masks, that were helpful in the short run, may have turned counterproductive by changing the intra-host selective environment. Ultimately Covid is bound to become just another common cold virus and the progress in that direction is clearly visible. There is no other likely fate of the pandemic. The question is whether we could have facilitated the rate of this evolution. My gut feeling is yes, we could have, by implementing better designed and carefully optimized preventive measures. But not only data needed for this optimization is absent, even such a concept is absent, so systematic studies in that direction are not even expected to happen. Evolution today is rich in molecular data but that comes as a cost of deteriorating insights into natural selection. During the Covid saga, there were plenty of talks and huge data about the mutations and the variants and their transmission, but little insights into how selection worked on the mutants being generated. There were some half baked ‘evolutionary’ statements. Someone said that by the preventive restrictions you can keep the viral population limited and thereby minimize mutants arising. But the question whether viral evolution is mutation limited or selection limited was never critically examined. Sound evolutionary thinking needs being open to alternative possibilities, insights into possible selective forces and a keen eye on the patterns in data. If such thinking becomes a part of preventive medicine, I am sure it will make handling of future epidemics more efficient.