Rapid response to Editorial 'Modelling the pandemic: reconsidering the quality of evidence from epidemiological models’
Dear Editor,
I was very interested in the BMJ Editorial 21st April, particularly the main title: Modelling the pandemic, a topic with multiple dimensions and potential output for tailoring intervention. I was also interested in the second rapid response letter noting different international “CoViD-19 life cycle curves”. Several reports reflect on geography and ethnicity as factors influencing the mortality and degree of prolonged morbidity from COVID19. A recent UK report was the 7th May UK Office of National Statistics brief online publication of comparative UK death-rates from COVID-19 (Syn. SARS-CoV-2), noting significant differences in mortality between different ethnic groups, after adjusting, by location, for socioeconomic and population density issues. Another report, currently in preprint (https://doi.org/10.1101/2020.05.06.20092999), presents a detailed analysis of COVID-19-related hospital deaths among adult NHS patients, finding ethnicity an important factor.
The differential international pattern of case-fatality and prolonged morbidity rates is clearly apparent in current academic online sites, derived from multiple online data sources (e.g. https://coronavirus.jhu.edu) and is consistent, on a global basis, with a genetic-susceptibility effect. Mainland Southeast Asia (MSEA), where most coronavirus species originate and exist, consistently shows much lower or even zero national case-fatality rates and much-less persistent morbidity rates from COVID-19 than elsewhere in the World. For instance, useful running summary histograms from one of those online sources most currently (10 May), show Singapore with 23,822 COVID-19 cases diagnosed since the index case on 23rd January 2020, but no deaths, and only 1097 cases still hospitalised (https://en.wikipedia.org/wiki/COVID-19_pandemic_Singapore). Comparisons with other nations, can be made by changing the nation in the link.
We all need an effective vaccine, but there has been concern widely expressed, that the first vaccines currently being trialled might not necessarily give solid immunity to all, perhaps because of some hypothetical lack of specificity in some of our immune systems. While the above regional and ethnic differences predict an even greater tragedy unfolding amongst some populations, particularly of African ancestry, they also offer some opportunity for a targeted, safe, engineered vaccine that could lend that putative innate MSEA COVID-19 protection to all of us irrespective of origin. Excitingly, preliminary evidence of that possibility and the practical components of its solution have already been offered in several published reports - see below.
It is proposed here that a COVID-protective genetic locus can be identified in the human Major Histocompatibility Complex (MHC) where our adaptive immunity engine resides. On statistical inference, there is a clear candidate locus, namely human leukocyte antigen allele group HLA-A*11, which is present at very high allele frequencies in most MSEA populations: ~0.30-0.58 [1] i.e. phenotypically detectable in ~50%-90% of individuals. However, HLA-A*11 is absent from all Sub-Saharan populations tested and in most individuals of recent African ancestry living elsewhere. It was postulated that HLA-A*11 was acquired from archaic Denisovans after the ancestors of modern Eurasians left Africa [1]. Amongst W. Eurasians Its allele frequency is ~0.05-0.1, with correspondingly low overall phenotypic frequencies, and ~0.07-0.2 allele frequencies are observed in S. Asians [1] Presumably HLA-A*11 was strongly selected for in survivors of local disease. (see also World map of allele frequencies: www.allelefrequencies.net/hla6008a.asp?hla_allele=A*11: )
Bats may be the main host of coronavirus sp. [2] as the multiple zoonotic coronavirus species recently found in a bat & bat-guano survey in central Myanmar imply: 6/7 coronavirus species identified were novel and local to Myanmar and all those are yet to be identified in a human host [2]. Whether MSEA is/was the main virus homeland is another matter.
In experimental support of specific HLA-A*11 enhanced protection, HLA-A*11:01 binds particularly well with a unique nucleocapsid protein peptide found in all SARS-CoV isolates [3][4], indicating potential for peptide-epitope engineered vaccine-development. This last is theoretically feasible; for instance, a direct practical experimental approach found that adjuvanted multi-epitope vaccines protected HLA-A*11:01 transgenic mice against another Worldwide zoonosis Toxoplasmosis [5].
Given the urgency, difficult questions include: How easy and speedy would it be to:
1) Engineer and experimentally test a hypothetical bespoke vaccine (or any other epitope-engineered vaccine for that matter) - and 2) then progress to ethical trial in humans – in parallel or after trials of more ‘off-the-shelf’ vaccines currently under approved trial?
Stephen Oppenheimer (FRCP retired.)
Green Templeton College, Oxford
[1] Abi-Rached L, Jobin, MJ, Kulkarni, S, (& 20 others). The Shaping of Modern Human Immune Systems by Multiregional Admixture with Archaic Humans. Science. 2011; 334 10.1126/science.1209202
(see also World map of allele frequencies: www.allelefrequencies.net/hla6008a.asp?hla_allele=A*11: Note- the same webpage www.allelefrequencies.net/ also has an large table of worldwide individual population frequencies accessible by searching for the same A*11allele).
[2] Valitutto M, Aung O, Tun KYN (& 15 others). Detection of novel coronaviruses in bats in Myanmar. PLoS ONE (2020) 15(4): e0230802. https://doi.org/10.1371/journal.pone.0230802
[3] Blicher T, Kastrup JS, Buus S & Gajhede M. High-resolution structure of HLA-A*1101 in complex with SARS nucleocapsid peptide. Acta Crystallographica Section D. (2005). D61, 1031–1040
[4] Prachar M, Justesen S, Steen-Jensen DB, Thorgrimsen S, Jurgons E, Winther O, and Bagger FO. COVID-19 Vaccine Candidates: Prediction and Validation of 174 SARS-CoV-2 Epitopes. bioRxiv preprint doi: https://doi.org/10.1101/2020.03.20.000794
Rapid Response:
Rapid response to Editorial 'Modelling the pandemic: reconsidering the quality of evidence from epidemiological models’
Dear Editor,
I was very interested in the BMJ Editorial 21st April, particularly the main title: Modelling the pandemic, a topic with multiple dimensions and potential output for tailoring intervention. I was also interested in the second rapid response letter noting different international “CoViD-19 life cycle curves”. Several reports reflect on geography and ethnicity as factors influencing the mortality and degree of prolonged morbidity from COVID19. A recent UK report was the 7th May UK Office of National Statistics brief online publication of comparative UK death-rates from COVID-19 (Syn. SARS-CoV-2), noting significant differences in mortality between different ethnic groups, after adjusting, by location, for socioeconomic and population density issues. Another report, currently in preprint (https://doi.org/10.1101/2020.05.06.20092999), presents a detailed analysis of COVID-19-related hospital deaths among adult NHS patients, finding ethnicity an important factor.
The differential international pattern of case-fatality and prolonged morbidity rates is clearly apparent in current academic online sites, derived from multiple online data sources (e.g. https://coronavirus.jhu.edu) and is consistent, on a global basis, with a genetic-susceptibility effect. Mainland Southeast Asia (MSEA), where most coronavirus species originate and exist, consistently shows much lower or even zero national case-fatality rates and much-less persistent morbidity rates from COVID-19 than elsewhere in the World. For instance, useful running summary histograms from one of those online sources most currently (10 May), show Singapore with 23,822 COVID-19 cases diagnosed since the index case on 23rd January 2020, but no deaths, and only 1097 cases still hospitalised (https://en.wikipedia.org/wiki/COVID-19_pandemic_Singapore). Comparisons with other nations, can be made by changing the nation in the link.
We all need an effective vaccine, but there has been concern widely expressed, that the first vaccines currently being trialled might not necessarily give solid immunity to all, perhaps because of some hypothetical lack of specificity in some of our immune systems. While the above regional and ethnic differences predict an even greater tragedy unfolding amongst some populations, particularly of African ancestry, they also offer some opportunity for a targeted, safe, engineered vaccine that could lend that putative innate MSEA COVID-19 protection to all of us irrespective of origin. Excitingly, preliminary evidence of that possibility and the practical components of its solution have already been offered in several published reports - see below.
It is proposed here that a COVID-protective genetic locus can be identified in the human Major Histocompatibility Complex (MHC) where our adaptive immunity engine resides. On statistical inference, there is a clear candidate locus, namely human leukocyte antigen allele group HLA-A*11, which is present at very high allele frequencies in most MSEA populations: ~0.30-0.58 [1] i.e. phenotypically detectable in ~50%-90% of individuals. However, HLA-A*11 is absent from all Sub-Saharan populations tested and in most individuals of recent African ancestry living elsewhere. It was postulated that HLA-A*11 was acquired from archaic Denisovans after the ancestors of modern Eurasians left Africa [1]. Amongst W. Eurasians Its allele frequency is ~0.05-0.1, with correspondingly low overall phenotypic frequencies, and ~0.07-0.2 allele frequencies are observed in S. Asians [1] Presumably HLA-A*11 was strongly selected for in survivors of local disease. (see also World map of allele frequencies: www.allelefrequencies.net/hla6008a.asp?hla_allele=A*11: )
Bats may be the main host of coronavirus sp. [2] as the multiple zoonotic coronavirus species recently found in a bat & bat-guano survey in central Myanmar imply: 6/7 coronavirus species identified were novel and local to Myanmar and all those are yet to be identified in a human host [2]. Whether MSEA is/was the main virus homeland is another matter.
In experimental support of specific HLA-A*11 enhanced protection, HLA-A*11:01 binds particularly well with a unique nucleocapsid protein peptide found in all SARS-CoV isolates [3][4], indicating potential for peptide-epitope engineered vaccine-development. This last is theoretically feasible; for instance, a direct practical experimental approach found that adjuvanted multi-epitope vaccines protected HLA-A*11:01 transgenic mice against another Worldwide zoonosis Toxoplasmosis [5].
Given the urgency, difficult questions include: How easy and speedy would it be to:
1) Engineer and experimentally test a hypothetical bespoke vaccine (or any other epitope-engineered vaccine for that matter) - and 2) then progress to ethical trial in humans – in parallel or after trials of more ‘off-the-shelf’ vaccines currently under approved trial?
Stephen Oppenheimer (FRCP retired.)
Green Templeton College, Oxford
[1] Abi-Rached L, Jobin, MJ, Kulkarni, S, (& 20 others). The Shaping of Modern Human Immune Systems by Multiregional Admixture with Archaic Humans. Science. 2011; 334 10.1126/science.1209202
(see also World map of allele frequencies: www.allelefrequencies.net/hla6008a.asp?hla_allele=A*11: Note- the same webpage www.allelefrequencies.net/ also has an large table of worldwide individual population frequencies accessible by searching for the same A*11allele).
[2] Valitutto M, Aung O, Tun KYN (& 15 others). Detection of novel coronaviruses in bats in Myanmar. PLoS ONE (2020) 15(4): e0230802. https://doi.org/10.1371/journal.pone.0230802
[3] Blicher T, Kastrup JS, Buus S & Gajhede M. High-resolution structure of HLA-A*1101 in complex with SARS nucleocapsid peptide. Acta Crystallographica Section D. (2005). D61, 1031–1040
[4] Prachar M, Justesen S, Steen-Jensen DB, Thorgrimsen S, Jurgons E, Winther O, and Bagger FO. COVID-19 Vaccine Candidates: Prediction and Validation of 174 SARS-CoV-2 Epitopes. bioRxiv preprint doi: https://doi.org/10.1101/2020.03.20.000794
[5] Bissati KE, Chentoufi AA, Krishack PA, Zhou Y, Woods S, (& 21 others). Adjuvanted multi-epitope vaccines protect HLA-A*11:01 transgenic mice against Toxoplasma gondii
JCI Insight. 2016;1(15):e85955. doi:10.1172/jci.insight.85955.
Competing interests: No competing interests
Competing interests: No competing interests