Even though case and death reporting has certainly been less reliable in Africa, there has been very little evidence of increased overall mortality or widespread COVID-19 disease, with the exceptions of South Africa and northern African countries. We now examine what could possibly explain this somewhat perplexing situation.
3.1. Demographic Pyramid
It is beyond doubt that the demographic pyramid is significantly related to decreased COVID-19 burden. It is well documented that COVID-19 burden is heavily skewed towards older populations [
107,
108], as demonstrated by a study of 17 million COVID-19 cases [
109]. Compared with a reference demographic group of 5–17 years, the demographic of 65–74 years is 35 times more likely to become hospitalized from SARS-CoV-2 infection, and 1100 times more likely to die from COVID-19, with these risks increasing significantly in even higher age groups [
108,
109]. Africa has the youngest population among all global regions, with a median age of 19.7 years [
25,
51]. Conversely, the median ages among the hardest hit countries are much higher: 26.8 years in India [
110], 31.4 years in Brazil [
111], 38.5 years in the U.S. [
112], and 40.5 years in the U.K. [
113]. Modelling clearly shows that the COVID-19 mortality for Africa tracks this similar age pattern [
48,
54], and this is confirmed by actual current mortality data [
114]. Through conducting a simple linear regression to show between-region differences, regressing cumulative mortality per 1 million population on the ratio of population aged 65+ vs. aged 15–64, the R
2 = 0.283 is found, meaning that the variance in mortality accounted for by age structure is 28.3% () [
2,
75,
115]; the cumulative mortality figures used here are for the period since the beginning of the pandemic through 17 June 2021, as reported on
oneworldindata.org (accessed on 17 June 2021), which utilizes Johns Hopkins University Centers for Systems Science and Engineering COVID-19 data [
2]. These data provide evidence that despite the considerable spread of infection, COVID-19 disease and mortality burden in younger African populations is comparatively absent. However, South Africa shows a much higher mortality than many countries with a similar age structure, including India and Egypt, meaning that other factors are also at play.
Figure 1. This analysis is based on data extracted from
ourworldindata.org accessed on 17 June 2021, retaining data on countries with populations of at least 1 million, for which complete data were available for the analyses done. Among these countries, as one would expect, COVID-19 mortality is strongly correlated with age structure. Note the concentration of purple dots in the bottom left, indicating comparatively low COVID-19 mortality and young age structure among most African countries. The Pearson’s R
2 for cumulative COVID-19 mortality and the ratio of persons aged 65+ to those aged 15–64 is 0.283; for example, 28.3% of the between-country variance in cumulative COVID-19 mortality can be accounted for by age structure alone.
3.2. Pre-Existing Conditions
It is well known that people with pre-existing conditions, such as diabetes, chronic respiratory diseases, obesity, and hypertension have a greatly increased risk of moderate to severe complications from COVID-19 infection [
53,
116,
117]. Broadly, these conditions are considerably less prevalent in low income and lower middle income countries (LICs and LMICs) when compared to higher income countries (HICs) [
9,
118], providing an additional possible explanation for why COVID-19 burden is more reduced in the African continent. Indeed, African countries have a low prevalence of NCDs (only accounting for 29.8% of total burden of disease in SSA, with the majority of burden coming from infectious disease) [
119], compared to 88% in the US and 74% in Brazil [
120], which align with the impact of pre-existing conditions on increasingly severe complications and death from COVID-19 [
9,
116]. South Africa, which accounts for nearly 40% of all reported COVID-19 cases and deaths in the continent [
2], reports an exceptionally high burden of NCDs [
119,
121]. However, some research suggests that the prevalence of infectious disease can similarly exacerbate COVID-19 burden and may actually indicate that regions with high infectious disease and low NCD prevalence (such as in Africa) are not advantaged [
9,
25]. For instance, a recent cohort study in South Africa suggested that HIV was associated with a doubling of mortality risk of COVID-19 [
122]. This is potentially significant to consider in explaining why South Africa has a disproportionate COVID-19 burden in the continent, given that it also has the greatest number of people living with HIV/AIDS in the world [
123]. More studies are needed, however, before this potential association can be determined.
3.3. Trained Immunity
The phenomenon of trained immunity may be tempering the COVID-19 burden in the continent. Here, we focus on four elements underlying this hypothesis: (i) BCG vaccinations, (ii) exposure to varied commensal microorganisms, or the “hygiene hypothesis”, (iii) prevalence of infectious diseases, and (iv) historical use of herbal plants and remedies.
(i) Live vaccines activate innate immune systems, conferring protection against future infections from other pathogens [
124,
125,
126,
127,
128,
129], which researchers believe may have the potential to also attenuate consequences of infection with SARS-CoV-2 [
130]. Recent data suggest that regions with mandated BCG vaccinations have had lower COVID-19 disease burden [
131], which may speak to an association between BCG vaccination rate and population COVID-19 burden. Children vaccinated with BCG could have a lower infection risk with SARS-CoV-2 [
132], continuing well into adulthood. Interestingly, and applicable to COVID-19, BCG vaccination was shown to be especially protective against complications of other respiratory viral infections, supported by studies in Guinea-Bissau and South Africa [
133,
134]. Additionally, in rodent models, BCG reduces viral load from infection by influenza A and herpes simplex virus type 2 (HSV2) [
135,
136], with a mediation by a boosted innate, nonspecific immune defense via increased cytokine production and macrophage action. It is not known if BCG immunity confers such protection in older populations [
132], but this has been suggested by some research [
137]. This is hypothesized in part from observations in countries that lagged behind other efforts to disseminate BCG, such as Iran and Somalia, which have incurred a significant death toll from COVID-19. Still, it is possible that countries with earlier BCG administration campaigns have contributed to the protection of older populations from heavy COVID-19 burden, through childhood inoculation for tuberculosis [
137]. Because COVID-19 complications are often a result of significant systemic inflammation [
138,
139], the fact that inoculation with BCG boosts an innate immunity that subsequently lowers the extent of inflammation [
132] indicates that it could be a pathway by which BCG attenuates infection of SARS-CoV-2. Of course, controlled clinical trials are needed to verify this hypothesis. While this varies, most African countries have high BCG coverage [
140], with the notable exception of Somalia, due to the long-standing civil wars interfering with child vaccination programs. As noted in one study, countries without universal policies for BCG vaccination (such as Italy, the U.K., Spain, and the U.S.) have experienced much more severe disease burden compared to countries with universal programs (including most African countries and Japan, for example) [
137]. However, this association may be primarily due to other factors; for example, countries that have a BCG vaccine mandate may tend to have stricter public health measures in place that could indirectly affect population COVID-19 burden, instead of the effect being driven primarily by BCG vaccination. Furthermore, if this BCG hypothesis turns out to have some merit, countries in Africa with similar levels of BCG coverage and population structure should show comparable COVID-19 burden.
(ii) The so-called “hygiene hypothesis” posits that some environments advantage populations against certain forms of infection and disease, due to chronic exposure to a multi-microbial environment, potentially producing protective immune effects when encountering new pathogens [
130,
141]. There has been some concern regarding regions that use ultra-hygienic practices, exemplified by the overuse of hand sanitizer and other disinfection practices in many countries, as inadvertently creating a disadvantage for confronting new immune challenges such as SARS-CoV-2 [
130]. Accordingly, non-specific immunity would be weakened and may have implications for disrupting the adaptive composition of commensal organisms on the skin, gastrointestinal tract, and other organ systems [
130]. Because COVID-19 is a relatively new viral problem, it may take a while before conclusive statements can be made about the role of the microbial environment on infection susceptibility, but researchers agree that this hypothesis is plausible [
130], in part indicated by the aforementioned dichotomy of burden between richer and poorer countries [
142,
143]. Higher income countries (with a few exceptions) have suffered much greater COVID-19 burdens (specifically, hospitalization and death rates) than the poorest countries, on average [
2]. Such data raise the consideration that richer countries could be maladaptively over-sanitizing.
(iii) Given that 22 of the 25 most vulnerable countries to infectious disease epidemics are in Africa (the other three being Afghanistan, Haiti, and Yemen) [
144], the continent carries the heaviest burden of infectious diseases, including the impoverishing neglected tropical diseases (NTDs) [
145,
146]. During 2018 alone, SSA faced 96 disease outbreaks in 36 of 47 countries [
55]. This pathogenic environment precipitates the wide use of antibiotics, antimalarials, and other drugs to treat NTDs, such as azithromycin and ivermectin often distributed through mass drug administrations [
147,
148,
149,
150,
151], which might counteract to mitigate COVID-19 morbidity. In particular, used widely over several decades in SSA, ivermectin has been spotlighted as a potential treatment for COVID-19 [
152,
153], including by the NIH [
154,
155]. Researchers have postulated that “circulating viruses or parasites in the African subcontinent” could explain high SARS-CoV-2 antibody seropositivity [
14]. For instance, of 228 million cases of malaria worldwide in 2018, 93% were in SSA [
156]. Notably, South Africa is not generally endemic for malaria and other NTDs [
157]. Intense malaria exposure (which is frequent in many rural areas in SSA and much less so in urban areas, and not at all in South Africa or in northern Africa countries) has a strong influence on the immune system and could contribute to a better trained immunity [
158,
159]. It is possible that infection by malaria alone may overstimulate the immune system and confer an immune advantage when compared to nonexposed populations. To further investigate this potential role, as very few to no communities outside of Africa are holo-endemic for the disease [
160], mechanistic studies would be needed to determine if there is cross-immunity between malaria and SARS-CoV-2 exposure.
(iv) Yet to be measured, the historical use of natural medicine for primary care [
161,
162,
163] and widespread belief of self-medication with these for COVID-19 in Africa has triggered a WHO-AFRO expert panel in September 2020 to endorse a protocol for the clinical investigation of herbal medicine for COVID-19 [
164]. During 30 March–1 April 2021, the Third Regional Consultation with Experts and Researchers on the Contribution of Traditional Medicine to COVID-19 Response in the African Region was held, with contributions from scores of scientists and countries. The case for exploring natural medicine in the fight against COVID-19 is justified [
165]. Although African countries such as Madagascar have endorsed the wide use of a traditional therapeutic agent to fight COVID-19, there are no published scientific data that would lend support to this claim.
Clinicaltrials.gov (accessed on 7 July 2021) reports that several studies are underway, including Chinese traditional herbal medicines [
166]. The establishment in Africa of a Regional Expert Advisory Committee on Traditional Medicine for COVID-19 compromising 25 members speaks to the widespread use of and belief in herbal medicine as possible means of prevention or cure of COVID-19.
3.4. Genetics
Recent work suggests that there is a role for genetics in COVID-19 trajectory, and in differentially affecting separate populations [
167,
168]. Some genetic immunological factors could possibly be playing a role in shielding Africa from the brunt of the pandemic [
41]. For example, SARS-CoV-2 infects human cells largely through its interactions with the ACE2 receptor, involved in regulating blood pressure dynamics [
6,
117,
169]. Populations varying in the expression of the ACE2 protein may have different baseline ‘openness’ for infection. African people have been shown to respond less effectively to ACE inhibitors for treatment of blood pressure, and have less expression of ACE2; therefore, there is potential for a more difficult route that the virus must maneuver to infect cells in this population [
6,
169]. There also may be genetic susceptibility via the 3p21.31 gene cluster, as one GWAS study showed ABO blood group A as having the highest risk of COVID-19-associated respiratory failure, with group O having the lowest risk [
170]. Studies have shown that African populations have a particularly high proportion of O-positivity at nearly 50%, which is higher than in White and Asian populations [
171,
172,
173]. It is possible that this increased O prevalence could be conferring a greater protective effect in African populations compared with other groups with less O prevalence; however, no studies have concluded this. While this hypothesis is somewhat challenged by the particularly heavy COVID-19 burden facing African Americans in the U.S. [
174], who would likely share some or most of these genetic advantages [
175,
176], elevated levels of NCDs are observed more in African Americans than in continental African populations [
119,
177,
178], which could help explain this discrepancy along with other adverse socioeconomic and cultural factors.
3.5. Broader Sociocultural Implications
Importantly, inequality of distribution of income (standardized by the GINI co-efficient) appears to be at least partially correlated with increasing disease burden of COVID-19, as South Africa (with a value of 63.1, among the highest in the world) and Brazil (54.7) [
179] have been hit hard by COVID-19. One study of the top 50 countries with the highest numbers of cases suggests that increased income inequality was associated with increased severe cases and mortality [
53]. Across the US, Brazil, South Africa, and Europe, increased mortality has been reported among minority groups such as Africans and Asians [
180,
181]. Three countries (South Africa, Brazil, the U.S.) seem to have similar risk profiles: long historical cleavages of institutional racism and inequality [
182,
183] that exacerbate COVID-19 vulnerabilities among large Black populations. The role in which inequality and poverty play totally depends on the behavior and the biological/immunological factors that they influence. For example, in New York and in other U.S. cities, poor people have difficulty isolating themselves, as they commonly utilize public transportation, share living spaces with more people, work in crowded environments, and overall, have lower social mobility [
184]. In contrast, in many African cities, the social and political elites are the ones who can afford to live and work in airconditioned closed spaces, increasing susceptibility to infection through close, indoor contact with others [
185]. However, this should not be generalized as the case in every African country, as work has also pointed to the similar theme of poorer populations facing a higher burden, such as in South Africa, with the elites largely shielded from the virus [
186].
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Rapid COVID tests have proven to be a complete disaster.
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