When Edward Jenner, a young English doctor at the end of the eighteenth century, produced the first smallpox vaccination, he was unaware of the existence of viruses and immune reactions. He worked on the basis of simple observations, which concerned those who were sick, as well as those who were not.
It was examining those who were not ill – notably those young farm girls who milked cows and who only had benign pustules on their hands, but who never caught real smallpox – which guided him in developing a vaccination.
COVID-19 is a new illness and there are many aspects of its pathogenesis which we don’t understand. Even as its ravages continue, we are yet to find either a treatment or a vaccination.
With so many unknowns we are sometimes reduced – as was Dr. Jenner – to making simple observations.
In the case of COVID-19, we see that the illness strikes individuals and populations globally in very unequal ways. Explanations have been given for this very heterogeneous social and geographic incidence: the advanced age of the sick and the weakness of their immunity systems, the existence of comorbidities (cardiovascular and lung ailments, diabetes, obesity, inflammations), crowded living conditions, lack of hygiene, lack of access to medical care, etc.
But this is not enough to explain the differences in the responses of the immune systems of each individual, which cover cases varying from asymptomatic to lethal. It has been estimated that up to 80 percent of people in a given population overcome COVID-19 without even realising it, and that of the other 20 percent who have symptoms, either at home or in hospital, less than 1 percent die.
Comparing the impact of COVID-19 in different regions of the world allows the resistance of some populations, who are relatively spared by the pandemic or who even seem to escape it altogether, to be measured.
While the number of deaths per million inhabitants is in the hundreds in the most affected countries (Western Europe, North America, Brazil), it can be counted on the fingers of one hand in the least affected countries. Some countries where no deaths are attributed to COVID-19 appear to be completely spared. Even if official statistics are not always absolutely reliable, the scale of the disparity between these countries remains clear in the comparative statistics.
Factors such as climate (temperature, amount of sun, humidity), economic development, quality of governance, strength of the hospital system, health of the population, living standards as well as cultures and demography are, by themselves, not enough to explain the disparity of the impact of COVID-19 between countries and regions.
Take the case of my native Cambodia. The country appears to have all the preconditions for a terrible COVID-19 impact: extreme poverty, dilapidated hospital infrastructure, dreadful hygiene, overcrowded living and working conditions, especially for the hundreds of thousands of workers who come from the countryside and are grouped around the factories concentrated in urban centres. Further, the government in Phnom Penh, very close to that in Beijing, has not so far interrupted any air connections with China, including those from Wuhan, the starting point of the epidemic. There was reason to fear the worst when the autocratic Prime Minister Hun Sen declared on 18 February, right at the start of the pandemic, that COVID-19 would only reach Cambodia on the “31st of February”, or never. Such optimism combined with lack of planning led to fears of considerable numbers of victims due to the absence of precautions.
But five months later, in mid-July, while the number of deaths from COVID-19 is well over half a million globally, no death in Cambodia has been attributed to the illness. Apart from cases among foreigners, essentially tourists, the few dozen Cambodians who have caught COVID-19 have all recovered.
These official figures would have left me sceptical had they not been in line with data from neighbours Laos to the north and Vietnam to the east – especially the zero deaths they have reported. To the west, Thailand and Burma have extremely low death rates of 0.8 and 0.1 per million respectively.
Neither climate nor socio-economic factors can explain this. What do the populations of these five countries have in common that is protecting them? The answer takes us in an unexpected direction. “Hématologie Géographique” or “Geographical Hematology” was published in 1966 by two eminent French hematologists, professors Jean Bernard and Jacques Ruffié. Combining knowledge of history, geography, archaeology, hematology and genetics, the authors showed that numerous populations of South-East Asia carried hemoglobin E in their blood. This is a genetic characteristic of populations descended from the Khmer Empire, which was at its height in the 12th and 13th centuries. (1) (2)
Two facts must be pointed out:
1- Hemoglobin E is a factor of natural selection which has protected the populations which have it against the most serious forms of malaria, an endemic illness in the region since the dawn of time. (3) (4) (5) (6) (7) (8)
2- There are striking pathogenic similarities between malaria and COVID-19, especially in the shared symptoms in the most serious cases of the two illnesses: fatal sepsis stemming from a “cytokine storm”; formation of blood clots leading to thrombosis, pulmonary embolism and strokes; serious complications affecting multiple vital organs (brain, lungs, kidneys).
So the question is, if hemoglobin E has been able to protect its carriers against the worst forms of malaria, can it also give protection against the most serious cases of COVID-19, which has very similar worst-case symptoms?
The question is all the more worth asking as there exist other traits shared by the two illnesses. There exists notably a virus with animal origins which infects the parasite responsible for malaria and which has a genomic sequence quite similar to that of coronavirus, which could signify that the malaria-related virus might confer a form of immunity against COVID-19. (9) (10) (11) (12)
To seek to further verify my hypotheses on the relation between malaria and COVID-19 on one hand, and the protective role of hemoglobin E (and other possible hemoglobin variations) on the other, I extended my observations to India and Africa. (13)
Two points about India stand out. The first is that the zones with endemic malaria (in the centre-east and the north-east) seem to resist COVID-19 much better than the rest of the country. The second is that the seven small states of north-east India, where the most of the populations carry hemoglobin E like the neighbouring populations of Burma, seem to be the most spared by COVID-19, with exceptionally low or zero deaths.
For Africa, the main point is that the countries with endemic malaria in the central, sub-Saharan part of the continent resist COVID-19 better than north Africa’s countries and South Africa, which are not affected by malaria. (14)
The cases of India and Africa reinforce the hypothesis that I have formulated for South-east Asia, that malaria-infested regions suffer less from COVID-19 than areas without malaria. There may therefore be a relationship between the two illnesses in the form of immunity to malaria which may also give protection against COVID-19, or at least against its most serious forms.
This protection may take the form of hereditary immunity which manifests itself in variants (E, C and S) of hemoglobin in populations in malaria-infested areas. These hereditary hemoglobin variations contained in red blood cells allow better resistance to the pathogenic malaria agent, a parasite of the Plasmodium genus, which attacks these red blood cells.
These points are all the more interesting as recent studies show the role of other genetic factors in the variations between immune system reactions to coronavirus, which are also associated with red blood cells. So people with blood group O will be less susceptible than others to catch COVID-19. Specific genes have been identified and their role explained. (15)
But there exist multiple other genetic factors not linked to blood – such as certain enzymes or receptors present on the surfaces of other cells, tissues and organs – which mean that every person reacts differently to an attack from a pathogen such as coronavirus. These genetic factors explain why certain individuals and populations are not vulnerable to COVID-19, which points to a natural end to the pandemic without the necessity for “60 percent to 70 percent” of the population to build a “herd immunity” through catching the disease.
Asked why individual resistance to illnesses varies, Professor Jean Dausset, Nobel medicine prize winner in 1980 for his work on the human genome, answered: “The explanation is purely genetic. In all epidemics, part of the population is resistant, which leads to the extinction of the epidemic, as it runs out of people to kill …”. To illustrate his point, Jean Dausset recalled the history of the Great Plague and the saying: “They didn’t all die but they all caught it…”. (16)
Recognising the importance of genetic factors – such as those which are already evident in hemoglobin variations – in resistance to COVID-19, points to three courses of action:
1- Deepening research into the role of genetic factors in the pathogenesis of COVID-19 will greatly help in the search for treatments and a vaccination.
2- Epidemiological investigations using virological and serological tests in countries with little or no COVID-19 would give precious lessons on the nature and prevalence of these protecting genetic factors and help verify the hypothesis of natural immunity. There may be as much to learn from those who are not ill as from those who are.
3- Revision of the concept of “collective immunity” is needed once the importance of genetic factors, which naturally protect part of the population during a pandemic, is recognised. Because of these genetic factors, as Jean Dausset explained, an epidemic will run its course without a vast majority of the population having to contract the illness and acquire immunity as most people believe in the absence of a vaccination.
For the second time, I am calling for attention to be paid to the other face of the pandemic, meaning those who do not have the illness and those who are not at risk of getting it. The first time was to call for the creation of an immunity passport in my article “How to prevent Covid-19 from paralysing the world’s economy” in The Geopolitics on March 27. (17) Again, I am trying to focus attention on those who are not ill, not only to limit the economic damage, but in the hope of helping to combat the pandemic itself.
(1) “Hématologie Géographique – Écologie Humaine – Caractères Héréditaires du Sang”, by Jean Bernard and Jacques Ruffié, Masson et Cie, 1966.
(2) According to French professor of medicine Jean Bernard, former president of France’s Académie des Sciences: “The geography of hemoglobin E and that of the monuments of Khmer art are almost identical. This is a remarkable correspondence. The limits of the ancient Khmer empire were until now defined by archaeology. They can today be defined by hematology. The limits are about the same.”
(3) “Epidemiological studies indicate that hemoglobin E confers protection against severe malaria.”
(4) “Hemoglobin E, Malaria and Natural Selection: Our review shows that in vitro studies, evolutionary genetics studies and epidemiologic studies largely support an involvement of natural selection in the evolution of HbE and a protective role of HbE against malaria infection.”
(5) “Hemoglobin E (HbE) is distributed throughout much of Southeast Asia. Protection from malaria has been the conclusion of several studies.”
(6) “La résistance innée au paludisme due aux anomalies de l’hémoglobine: C’est une résistance génétique au cours de l’étape érythrocytaire qui a sélectionné des défauts génétiques du globule rouge comme l’hémoglobine E (HbE). Ce variant génétique responsable de la résistance au Plasmodium falciparum est transmis à la génération suivante.”
(7) “Influence of Hemoglobin E Trait on the Severity of Falciparum Malaria.”
(8) “Hemoglobin E: a balanced polymorphism protective against high parasitemias and thus severe P falciparum malaria.”
(9) “Novel RNA viruses associated with Plasmodium vivax in human malaria”
(10) “A Virus Hosted in Malaria-Infected Blood Protects against T Cell-Mediated Inflammatory Diseases,” which are reminiscent of COVID-19 and the reported ‘Cytokine storm’ syndromes.
(11) “Genomic similarity between the different strains of SARS- CoV-2 and the Matryoshka RNA virus 1 (MaRNAV-1) associated with Plasmodium vivax”
(12) “Why Indians might already have partial immunity against COVID -19? One of the factors giving them immunity could be that they are living in a malaria endemic region.”
(13) “Why Southeast Asia Is Relatively Spared by COVID-19”
(14) “Why Are Southeast Asia, India and Africa Relatively Spared by COVID-19?”
(15) “Individual differences in genetic makeup may explain our susceptibility to the new coronavirus and the severity of the disease it causes.”
(16) “La Mosaïque Humaine”, by Jean Bernard and Jean Dausset, Calmann-Lévy, 2000, page 202.
(17) “How to Prevent COVID-19 From Paralysing the World’s Economy”