By Rob Verkerk PhD, founder, executive and scientific director, ANH-Intl

Should we take note of India’s double mutants?

India’s a very large, highly populated country, the home of some 1.4 billion people – around 18% of the global population. It might have recorded some 166,000 deaths linked to covid – but that’s not a lot in relation to the total population. It only ranks 46^th in the league of per capita covid-associated deaths in the world based on our analysis of Worldometer data.

But now India is experiencing its second wave. The top genomics labs in India, working together as a consortium, have found nearly 800 ‘mutations of concern’ that are linked to the UK, South African and Brazilian lineages (B.1.1.7, B.1.351 and B1.1.28.1 respectively) of SARS-CoV-2. A whopping 15 to 20% of all positive samples analysed have been found to contain the double E484K and L452 mutations. Variants carrying the E484 mutation are not only more transmissible therefore aiding the spread of the virus in communities, they are also regarded as ‘immune escape’ mutations because they have been found to be capable of evading the human immune system. All very well if they stay put and don’t spread, not so good if they evade the immune system – especially not if it’s been primed by previous infection or vaccines.

KEY POINTS

• Rob Verkerk PhD revisits some of the issues raised by Dr Geert Vanden Bossche
• He asks how risky is it to rely on a single prevention strategy for covid-19 – in this instance mass vaccination?
• Using ecological arguments, he calls for an urgent diversification of strategies to build broader based natural immunity to combat continuing mutations of the virus
• He offers evidence that shows significant risks from the current strategies explaining why we need another 7 eggs in the covid prevention basket to protect against selection pressure driving mutations
• Diversification is key if we’re to prevent a human version of the environmental catastrophe predicted by Rachel Carson in ‘Silent Spring’ back in 1962 and get us off the vaccine treadmill

Evading the immune system

Here’s the thing. The immune system is exactly that - it’s a system, a very elaborate one at that, not a simple mechanism. For a respiratory virus to escape our immune system, it first has to be able to get round the physical and chemical barriers of our innate immune system that line our airways (and gut). Once through this outer barrier of defences, the spike protein needs to successfully bind to the ACE2 receptors in the outer cellular (epithelial) layer of our airways. Next it has to be able to avoid a diverse array of immune cells that either target the virus directly or wipe out cells containing replicating viruses that have successfully taken over the replication machinery of human cells, notably in the airways and lung tissues.

That’s a tough ask, any which way. Especially because the cells of our immune system have co-evolved alongside viruses for as long as our ancestors and mammalian relatives have been around. That’s somewhere around 250 million years of adaptation and co-evolution. Big name cellular players in the innate (‘first response’) side of our immune system are natural killer cells, macrophages and dendritic cells.

Especially because the cells of our immune system have co-evolved alongside viruses for as long as our ancestors and mammalian relatives have been around. That’s somewhere around 250 million years of adaptation and co-evolution.
- Robert Verkerk PhD

Once through the physical, chemical and cellular barriers of the innate immune system, a variant of the virus that is capable of evading the immune system has to then outsmart the two armouries of our adaptive (‘special forces’) immune system: the humoral (antibody) and cell-mediated (T cell) responses, respectively.

Most of the work that talks to immune escape, it’s fair to say, has studied just the first layer of armoury of the adaptive immune system – the humoral response, mediated by neutralising antibodies. Why? Many reasons – including the fact these are easier to study as you can readily measure antibody titres in blood or saliva samples, and neutralising antibodies have been the major markers for vaccine effectiveness as studied both in the Phase 3 trials and subsequently in ongoing post-marketing surveillance.

Neutralising antibodies literally block the virus from locking onto ACE2 protein that acts as the main protein for the two known SARS coronaviruses. These ACE2 receptors aren’t just found in the epithelial cells of our airways but also in the epithelial cell of our small intestine, arteries and veins, and in the smooth muscle cells of organs. That means if your immune system can’t put the brakes on the virus’ ability to replicate in the body, then there are lots of opportunities for the virus to get more of a foothold, increase viral load, and cause harm to the infected individual. From the virus’ perspective that’s all good and the shedding of virus particles then helps to build transmission chains between humans that maintain a healthy supply of hosts for the virus.     

Beyond antibodies and the humoral immune response

The downside of being over-reliant on antibody responses, either from naturally-acquired infection or from vaccines, is they’re short-lived. Levels of these antibodies peak around 2-4 weeks post symptomatic infection and while they might be detectable 3 months on, the lower amounts probably mean they’re a lot less effective at neutralising viruses.

We know from the six other coronaviruses that have made humans their hosts (4 of which can cause symptoms of the common cold) that long-term immunity comes not from antibodies, but from T cells. Two very important types of T cells are CD4 helper and CD8 cytotoxic T cells that can act as ‘memory T cells’. That means they learn from previous encounters with the virus, parts of the virus, related viruses or antigens delivered following vaccination, how to recognise and kill off cells containing specific proteins related to the offending pathogen. They also hang around for many years, probably more than a decade or even two – maybe even for life.

It might be that previous exposure to related coronaviruses and solid memory T cell responses provide cross-immunity explaining why so many people don’t get any symptoms, or experience only very mild symptoms, following SARS-CoV-2 infection.

What’s the exit strategy?

If there’s a common goal nearly everyone on the planet would like to see realised in order that we can restore some normality to our lives, it’s trying to make sure as many people as possible demonstrate a highly competent immune response. That means using the full force of the two sides of our multi-faceted immune when exposed to the virus.

The good news is that we know that the more competent someone’s immune response, the better they fare. But that can’t just be down to T cell responses because older people, who would have been exposed to more related coronaviruses than younger ones, generally fare worse. That’s because our immune systems become less competent with age – this process is called immunosenescence.

The good news is that we know that the more competent someone’s immune response, the better they fare.

- Robert Verkerk PhD

We also know it can’t just be down to antibodies, because a number of studies looking at this have shown there is no clear correlation between antibody titers and severity of symptoms. Men tend to have an elevated antibody response compared with women, and older people or people who get very sick and can have elevated responses compared those who’re infected with few or no symptoms.   

Building a multi-faceted immune armoury

Looked at from a holistic, systems or ecological perspective, if your goal is to minimise the severity of infection, including from new variants of the virus, you need to try to develop and prime your immune armoury across the board. You want what we call immune resilience – the real end game.

And this is where we feel the global strategy against this coronavirus is going wrong. There is just one very well-funded egg in the basket – and that’s covid vaccination.

Do we have signals yet to see how the greatest medical experiment ever conducted on our species is going to pan out?

Signals for caution

Three signals that point to the precariousness of a vaccine-dominant strategy against the virus are as follows:

• Mutations of concern. The independent development and spread of mutations of concern in geographically distinct parts of the world (notably the UK, South Africa and Brazil). Find out more here.
• Evolutionary selection pressure towards immune escape. The evolutionary convergence and spread of immune escape mutations that may also evade immunity conferred by covid vaccines and possibly even naturally-acquired infection. Find out more here, here and here.
• Potential for long-term downstream harms. The identification of an (albeit rare) autoimmune side effect of one of the vaccines (AstraZeneca). Find out more here.

You could write a book on each of these three areas – so we’ve left some references for those who’d like to delve deeper into each of these. Suffice to say each one of them is unpredictable given the complexity of the host-pathogen interaction, our different genetic make-ups, environments and behaviours.

Mutations based on substitutions (not deletions) could be ‘auto-corrected’ and wiped out after a short period and so expire. But that doesn’t seem to be happening with E484k (sometimes disaffectionately referred to as the ‘eek’ mutation). You only have to look at what is happening now in India, as mentioned in the opening of this article, and recognise the spread of the current array of variants that have all shown mutations that converge in the critical receptor-binding domain (RBD) of the spike (S) protein.  

When you hit a global population with a group of vaccines designed around a highly specific target in the form of a mutation-susceptible spike protein, vaccine resistance is as much of a potential problem as antimicrobial or pesticide resistance. Ecology and history provide us with some important teachings that are now crucially relevant to our current predicament...

Lessons from other fields

This brings us to the evolutionary argument of selection pressure. In short, this is the non-physical ‘pressure’ that is exerted between a virus, other pathogen or organism, that causes its evolution to move in a particular direction because of an interaction between variations in the pathogen or organism and factors in the environment.

It’s the reason that ‘pressure’ from antibiotics can lead to the increased survival and prevalence of bacteria that have acquired, through mutations, the genetic capacity to metabolise (detoxify) a specific antibiotic or family of antibiotics (antibiotic resistant bacteria). The same thing happens to insect pests that become resistant from overuse of pesticides on cotton, such as the armyworm.

The over-reliance on pesticides in agriculture has led many times over to a what has been called the “pesticide treadmill”- that’s the treadmill that farmers can find themselves on as a result of the selection pressure from pesticides that continues to drive the development of resistance in target pests, that in turn triggers the use of new pesticides, that then also select for those pests that, through their mutation-gifted ability to either better tolerate or resist the pesticide, lead to ever more resistant populations of pests. The treadmill might work well for agrochemical companies selling their wares, but it’s never been good either for farmers or the environment.

The vaccine treadmill?

The mainstream – one highly invested financially, politically and emotionally to a vaccine solution — tells us there is a way out: tweak the vaccines to cater for the new genetic variants, given that the frontrunner vaccines were all designed around the genome of the originally sequenced Wuhan virus.

Any evolutionary biologist worth his or her salt would tell you this is a risky road to traverse, especially if your vaccines are based on a very small protein component of the virus (the spike protein) that happens also to be the most subject to mutations of concern. That's undoubtedly the case in our current pandemic.

Can you just keep tweaking vaccines each year to stay up-to-date with the evolutionary journey of the virus, one that will always have some ability to evade the immune system if it is given sufficient opportunity to express its ‘error code’ (mutations). Like with the even more mutation-prone influenza A virus that's now had a 100 years to adapt to its host?

Do you change tack with the development of vaccines and make them more responsive to more proteins found in the virus, diverging from the near-exclusive focus on the spike protein? What about monoclonal antibody therapies – should these be abandoned in favour of polyclonal antibody therapies? And anyway, will these therapies consistently yield long-term memory T cell immunity?   

Or is the vaccine-dominated strategy destined to keep us locked into the vaccine treadmill?

No one knows for sure. But what we do know is that focusing on any single mitigation strategy is always risky. Made worse if you’re also measuring your success by using molecular testing systems such as PCR and lateral flow that will never show you’ve got on top of the virus. That’s because as prevalence gets lower and lower, your false positive rates go up - courtesy of the in-built errors in the diagnostic tests and Bayes’ theorem.

There's also the often unrecognised importance assumed by molecular testing of this one single pathogen. Molecular testing using PCR or lateral flow has seamlessly become a surrogate for disease incidence during the covid era. For all of human history a 'case' was a case of disease. That makes sense when you're interested in the health of people - because if you're healthy, you're healthy - irrespective of whether you have one or many thousands of distinct microorganisms within you, a tiny proportion of which may in certain circumstances become pathogenic (disease-causing).

Modern day epidemiologists, especially since the arrival of covid-19, now not only track disease incidence, disease severity and mortality. They track cases of infection - whether real or anomalous. Worse than that, politicians now make decisions based on what they consider to be cases of infection, with very little idea of whether the supposed infections are genuine (i.e. true or false positives), whether the infections are transmissible (which will depend on the viral load in an individual, among other factors), or whether the positive test result was flagged by non-viable fragments of viral proteins that have zero capacity to infect or replicate.

All of this greatly complicates any attempt to successfully exit this pandemic - especially as governments become progressively more tyrannical and authoritarian.    

Solutions lie in diversity

Complexity and uncertainty are the two things guaranteed in this host-pathogen interaction. If only it were simpler. But we know, for instance, that a robust T cell response with a negligible innate and antibody response can successfully clear (sterilise) virus from a host. We also know high antibody titres are no guarantee of successful neutralisation of viral particles. And that innate immunity in children and younger people can be a major reason for their tolerance of infection. We also know that everyone who has a compromised immune system fares less well than those with healthy, competent immune systems.    

Given that immune escape variants are becoming more widely distributed – can we really put just the one egg in our basket, in the hope that the now-promised tweaked vaccines will deliver the necessary immune response to quell the current crop of circulating variants? Can they really deliver the equilibrium in the host-pathogen relationship so many are desperately hoping for? 

Adding another 7 eggs to the basket

Herein lies the central place where the views of most natural health advocates diverge from those who are predisposed to unilateral solutions such as vaccines or monoclonal antibodies: our immune systems can be manipulated in ways that make them more competent in the face of infection by all variants of SARS-CoV-2 (as well as other pathogens).

Among these strategies that help support more competent, broadly-based and resilient innate and adaptive immune responses are those that reverse epigenetic ageing. These include:

1. A healthy, varied and diverse diet and healthy lifestyle
2. Vitamin D supplementation (or ample sunshine)
3. Vitamin C supplementation
4. Zinc supplementation
5. Magnesium supplementation
6. Ivermectin plus quercetin, melatonin, vitamin D and vitamin C supplements
7. Beta glucans supplementation.

Recognition of the importance of diversity has belatedly become de rigeur socially and environmentally. The same broadmindedness is now desperately needed in the new age of politicised medicine that took the world by storm some 12 months ago.

Or we might never be weaned from the treadmill that has been presented to us as a solution that potentially takes us into a human version of the environmental catastrophe that Rachel Carson warned the world about in 1962 if intensive pesticide use wasn't curtailed. 

>>> Find out more in our Covid – Adapt Don’t Fight campaign