13 Jan 2021 Episode 100 COVID in Africa

Dear colleague,

The first “perspective” (Ep 100-1) summarizes my feeling, when I try to understand “from a distance” what COVID means it Africa: it is “puzzling”.  Slide 2 shows an overview of the confirmed diagnoses and deaths.  It suggests that the epidemic in Africa took off later than in Asia, the Americas and Europe, it reached a first peak in July, then slowed down and now seams to enter a second wave.  But what is most striking is the very low African numbers as compared to the rest of the world (slide 3).  What are the reasons for this discrepancy?

The paper lists the following possibilities

1. Limited testing (which limits detection and isolation, and thus public health measures),
2. A much younger population (and thus fewer severe cases and deaths),
3. Climatic differences (which could affect transmission),
4. Preexisting immunity,
5. Genetic factors,
6. Early implementation of public health measures, and timely leadership.

In addition, I would investigate what is known about

7. Comorbidities and complications of COVID in Africa
8. Vaccine policy
9. Collateral effects of COVID

Let’s see what evidence can be found in the recent literature.

1. Limited testing

Slides 4-7 provide some data on individual countries: very striking is that most African, cases have been diagnosed in a single country: South-Africa. While countries with equally important or much bigger population size, such as Kenya and Nigeria, hardly contribute to the overall numbers. 

Slide 8 shows the data on deaths and diagnoses on 11 Jan 2021 in absolute and relative numbers.  In relative numbers Belgium has about 3 times as many deaths and diagnoses as South-Africa and about 100 times as many as the other selected African countries. 

Now, these African countries were selected, because they are the ones (I could find) with also some data on seroprevalence, taken during the “first wave”.  It is especially striking that already at that time, the seroprevalence in HCW in South-Africa (10.4 %); Malawi (12 %) and Nigeria (45%!!!) was clearly higher than in contemporary Belgium (around 8 %). In the “general population” (blood donors, households) it was 3.8 % in Mozambique, 4.3 % in Kenya and around 5 % in Belgium.  Togo had very low seroprevalence.

Unfortunately, I could not find more recent seroprevalence data for African countries, but presumably they have gone up with the second wave, just like in Belgium. (for reference see Ep 100 2-7)

Obviously, we are not sure to what extent the data are really valid, but the very big discrepancy between seroprevalence and cumulated confirmed (PCR) diagnoses (6 months later) in most African countries (except South Africa) indicates that the real size of the epidemic is order of magnitude larger than the officially diagnosed cases suggest and may be comparable with Europe.    

2. The population structure

Slide 11 is self-explanatory : South Africa has a different population structure, with more “middle aged” people than the other African countries and, in fact, seems to evolve towards a “European (Belgian)” like pattern.  This can partly explain why there are few COVID deaths in the rest of Africa and an “intermediary” death rate in South Africa. 

In that regard an African colleague wrote us last week:

“I have one concern that the average figure is masking the reality in different age-groups. 

Death rate among the elderly in Africa is similar to that in Europe and America. It is important that granular data is also provided. 

This is important as aged-care centers and nursing homes are almost nonexistent in Africa. You can find three or four generations living in the same household. There will be easy transmission of the virus from the young to the older. 

In this context, it is vital to implement household masking to prevent transmission to the elderly. 

I hope the regional CDC and WHO will also advise countries to target and shield this population group.”

3. Influence of climate  While the climate in South-Africa is more moderate, it is of course south of the equator, hence now “summer time”. Therefore, you would not expect a more severe “second wave”, based on climate and yet there is a substantial second wave ongoing…

4.   Pre-existing immunity?

4.1. The perspective by Mbow et al (Ep 100-8) provides some speculations on why COVID seems to hit Sub-Saharan Africa less than other continents. These authors point to often mentioned hypotheses about the importance of “trained immunity” (see the BCG story, which remains unproven until now),  “virtual memory” (activation of potentially useful T cell clones by helminth infections) and “hygiene hypothesis”, which is a variant of “trained immunity”: children who are more exposed to microbes in their early live will develop less allergies and react better to pathogens, where you need a “Th1” response (Interferon-gamma driven activation of macrophages and cytolytic T cells).

There is a whole literature on differences in immune parameters between Africans and Europeans, but it is equally true that Africans, despite BCG vaccination and all kinds of “training”, do suffer a lot from tuberculosis, HIV, malaria, hepatitis B and C, all types of Herpes viruses, helminths etc.   The basic idea of the proponents of the above hypotheses seems to be: “What doesn’t kill you, makes you stronger”.  But is that really so? 

In fact, it is well known that many chronic or recurrent infections, such as malaria, hepatitis B/C, CMV etc… induce “polyclonal activation” of T and B cells (with hypergammaglobulinemia).  And this polyclonal activation in fact resembles (or even leads to) “immunosenescence”: it is a kind of “refractory” state, where people react less efficiently to new antigens. So, I’m awaiting proof that in the case of SARS-CoV-2, this would be different….    

4.2. Another aspect is the possibility of more specific cross-immunity.  Maybe (beta-) corona viruses are circulating in Africa and provide a level of cross-protection?  I could find one paper by For Yue Tso (Ep 100 – 9), comparing pre-COVID plasma from blood donors in USA, Tanzania and Zambia (some were HIV+) see slide 12. 

- Clearly, a substantial cross-reactivity with SARS-CoV-2 nucleocapsid was seen in the African samples (10-15 %), while almost absent in USA.  Those sera reacted mostly against the common Coronaviruses NL63 and 229 E. 

- Conversely the cross-reactivity against Spike was limited (3-4 %), but all those samples also reacted against all common coronaviruses. 

So, there is some level of cross-reactivity, but whether that will suffice to have any protective effect against SARS-CoV-2 remains to be shown.  In this study, immunofluorescence was used, which may not be very sensitive and it is a study on adults.

I want to remind the very remarkable study by Ng in Science, carried out in UK, where a number of very sensitive tests were used (Ep 100-10). They show that cross-reactive anti-SARS-CoV-2 Spike S2 portion  antibodies are very common in children and adolescents. These Ab are rather potent in a pseudovirus neutralization test. (Slide 12)

Clearly, we need  more data to judge about the significance of cross-reacting antibodies (and T cells).  And, again, this cross-reactivity may have a different meaning according to age and general immune background: it is more likely that such cross-reactivity would function better in a “young and fresh” immune system than in an “old or over-activated” immune system…. What all that finally means for Africa and COVID remains to be seen….

5. Genetic factors

5.1. Viral genetics: I found two papers on the phylogenetic analysis of the SARS-CoV-2 variants in Africa (Ep 100-11 and 12).  They agree that the most prominent source of the viral introductions is Europe (43 % of a total of 211 introductions) and that fewer (80) spread between African countries. These 2 papers seem to disagree about the name of the dominant lineage: A-A2 according to  Gomez-Carballa (Ep 100-11) and B1 according to Lu Lu (Ep 100-12).  Interestingly 95 % have the D614G mutation.  The representativity of the samples is flawed as 56 % originates from South-Africa. 

Obviously, since these 2 papers were published, the new aggressive variant B.1.351 lineage, sharing the N501Y mutation with the UK variant emerged in South-Africa and has started spreading to other countries (Ep 200-13).

5.2. With regard to human genetic factors, one can speculate a lot about the known higher genetic variability of Africans, as compared to Europeans and Asians, because this could indeed explain relative or absolute resistance of particular African populations towards particular infections.  But there is simply no data.  However, as Mbow (Ep 100-8) suggests: if African-Americans are a proxy of (genuine) Africans, there is no reasons to think that they would be resistant to SARS-CoV-2 (African-Americans are harder hit by COVID than other US citizens).

There is just this one paper by Huang (Ep 100-14), suggesting that the relatively low expression of the ACE-2 (the SARS-CoV-2 receptor) by both Europeans and Africans, could explain why the D614G variant is so dominant in these continents.  But that is a relative argument: with regard to Africa, it could just be a “founder effect” (as so many introductions came from Europe).

6. Early implementation of public health measures, and timely leadership.

This is a highly “political” issue. I leave it to Public Health specialists to discuss it.

Pilay (Ep 100-15), however, shows that the easing lockdown on June 1st in Gauteng (a small but densely populated SA province with Joburg) had a dramactic increasing effect of the COVID “attack rate” (the percentage positive tests): from 4 % to 20 %.  

7. Comorbidities and complicationsA very thorough analysis in Western Cape among 3,460,932 public sector patients (16% HIV positive), 22,308 were diagnosed with COVID-19, of whom 625 died. (Ep 100-16 – Slide 17)

• HIV increased risk of COVID-19 mortality (adjusted hazard ratio  [aHR]:2.14, with no clear difference according to viral load; increased risk when CD4 T < 200 and
• Current and previous tuberculosis also increased COVID-19 mortality risk (aHR 2.70)
• Some “traditional (NCD) risk factors” such as age and uncontrolled diabetes carry a higher risk than either HIV or TB, while hypertension and chronic kidney disease have a similar risk as HIV or TB.  Remarkably, chronic pulmonary disease and asthma showed no increased mortality risk.

1. 2. The narrative review by Anjorin (Ep 100-17) attracts attention for other infectious comorbidities (besides HIV-TB and NCD). 

First, the status of malaria as a common cause of fever may lead to underdiagnosis of COVID-19, even in the presence of malaria parasites.

Moreover, viral pneumonia in general is often complicated by various viral, bacterial and fungal coinfections and that also applies to COVID. Data from available studies show that most coinfections occur in critically ill patients and those with preexisting medical conditions and are associated with high mortality. 

Finally, undernutrition, especially in children and elderly is prevalent, is associated with immune deficiency, hence could favor COVID-19 disease. Conversely, COVID-19 could also worsen malnutrition in vulnerable people.  

However, no hard data on Africa are presented. It is rather a research agenda.

1. 3. Ezeokoli  (Ep 10-18) attract attention on fungal co-infections (Aspergillus, Cryptococcus and Candida) which are particularly prevalent in HIV patients.  Since HIV is common in South-Africa, they suspect that fungal infections could be an important cause of death for COVID patients. 

8. Vaccines:the papers 19 and 20 point to:

• Failure of the WHO COVAX initiative to live up to the promise of procuring low- and middle income countries with vaccines
• China  is filling the gap that the Western countries leave in Africa

Besides, the “Western” forerunners (mRNA and vectors) have higher requirements than the Chinese inactivated vaccines, with regard to cold chain

9. Collateral effectds:

9.1. Conclusion from Pilay (Ep 100-15): … the low incidence of COVID-19 during this time must be measured against the potential ‘side-effects’ of a hard lockdown. Malnutrition, lack of access to chronic medication, delayed presentation of illnesses and gender-based violence may all have contributed significantly to overall morbidity and mortality. The potential for excess deaths and ‘net harm’ as a result of the indirect impact of lockdown measures needs to be considered by policymakers.

9.2. A personal testimony from a Guinean refugee: while schools remained open during the EBOLA epidemic in 2015-2016 (2500 deaths), they are closed since March 2020 (although Guinea has only 81 COVID deaths as of 13 Jan 2021.

9.3. Perspective in Science on potentially dramatic effect of COVID on cancer control (Ep 100-21)

9.4. A positive effect: less traumatic accidents and violence in South-Africa during lockdown (Ep 100-22 and slide 19).  Nevertheless, relatively more women were victim of “blunt assault and penetrating trauma” (= domestic violence?).

9.5. “Make a virtue out of necessity”: Molyneux (Ep 100-23): Some of the COVID measures on increased hygiene etc are also useful in the control of neglected tropical diseases, but should be combined with sustained support for mass drug administrations (for control f helminths in school children)

“…the importance of hand and face washing and improved sanitation—a common strategy for several NTDs that also reduces the risk of COVID-19 spread.

This so-called “hybrid approach” will demonstrate best practices for mitigating the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) by incorporating physical distancing, use of masks, and frequent hand-washing in the delivery of medicines to endemic communities and support action against the transmission of the virus through water, sanitation and hygiene interventions promoted by NTD programmes”

Best wishes,

Guido