key: cord-1054402-tc3qptp6
authors: Gobe, I.; Koto, G. F.; Molebatsi, K.; Mokomane, M.; Kasvosve, I.; Motswaledi, M. S.
title: Vaccination for some childhood diseases may impact the outcome of covid-19 infections
date: 2020-09-03
journal: nan
DOI: 10.1101/2020.09.02.20186528
sha: f26acd7473ad669c1693f72fae87eb96a171bd38
doc_id: 1054402
cord_uid: tc3qptp6

Background: COVID-19 found the world in a state of unpreparedness. While research efforts to develop a vaccine are on-going, others have suggested the use of available vaccines to boost innate immunity. Objective: We analysed three databases: UNICEF Immunization Coverage, Worldometer Corona Virus Updates and World Bank List of Economies to establish the association, if any, between vaccination for various diseases and COVID-19 death rates and recoveries across world economies. Results: Mean percentage death rates were lower in countries that vaccinated for Hepatitis-B birth dose (2.53% vs 3.79%, p = 0.001), Bacille Calmette-Guerin Vaccine (2.93% vs 5.10%, p = 0.025) and Inactivated Polio Vaccine 1st dose (2.8% vs 4.01%, p = 0.022) than those which did not report vaccination. In high income countries, a significant negative correlation with death rates was observed with vaccination for Measles-containing vaccine 2nd dose (r = -0.290, p = 0.032), Rubella- containing vaccine 1st dose (r= -0.325, p = 0.015), Hepatitis B 3rd dose (r = -0.562, p = 3.3 x10-5), Inactivated Polio vaccine 1st dose (r = -0.720, p = 0.008). Inactivated Polio Vaccine 1st dose and Measles-containing vaccine 2nd dose also correlated with better recoveries. In Low Income countries, only Rubella-containing vaccine correlated with lower deaths while Yellow fever vaccine was associated with poorer recoveries. Conclusion: Our analysis corroborates the potential benefit of vaccination and warrant further research to explore the rationale for repurposing other vaccines to fight COVID-19.

A number of recent publications have raised conversations regarding the potential benefits of BCG 31 vaccine in mitigating the adverse effects of SARS COV-2 infection (1, 2) . Such hypotheses were inspired 32 by past reports where BCG vaccination was observed to have benefits beyond prevention of 33 tuberculosis alone. These included protection against some viral infections(3) as well as overall 34 reduction in childhood mortality occasioned by other infectious agents(4). A recent publication based 35 on country policies reported that countries with a long history of BCG vaccination experienced lower 36 numbers of SARS COV-2 infections and fewer deaths (1) . Another study found a strong correlation 37 between the BCG index and reduced COVID-19 mortalities in European countries (5). 38

While most vaccines confer immunity through antigen-specific immune responses, some reports 39 suggest that vaccination against one disease may confer protection against another, as evidenced in 40 the upregulation of a wide range of innate immune responses to BCG vaccine(6). This phenomenon is 41 attributed to the development of "trained" immunity, in which BCG-activated monocytes are primed 42 to produce more cytokines such as IL-1β, IL-6, IFN-γ and TNF(2). 43

In fact, other investigators have reported increased expression of pathogen-associated molecular 44 patterns on cells of monocytic origin up to one year after exposure to BCG, enabling a more robust 45 induction of TH1/Th17 responses(7). BCG vaccination was also noted to enhance production of such 46 cytokines as IFN-ƴ, IL-2 and IL-12, which are important for potentiation of cell mediated immunity(8). 47

The above notwithstanding, other investigators have cast doubt on the potential benefits of BCG 48 vaccination in the fight against COVID-19(9). 49

The afore-mentioned discussions have inevitably culminated on the debate to consider the potential 50 prophylactic use of BCG against COVID-19(10), with some data corroborating the anti-COVID-19 51 effect(11). In the current report, we analysed global vaccination coverage and global COVID-19 data 52 to determine if any association existed between the degree of vaccine coverage and the death rates 53 attributed to COVID-19, as well as recovery rates. 54 . CC-BY-ND 4.0 International license It is made available under a perpetuity.

is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 3, 2020. The death rate for each country was computed as the total number of deaths per million divided by 64 the total number of confirmed cases per million, expressed as a percentage. The independent samples 65 t-test was used to compare the mean percentage of COVID-19 deaths between countries that 66 reported vaccinations and those which did not, using data extracted on the 3 rd August 2020 from the 67 COVID-19 Worldometer. Death and recovery data were available for 168 and 175 countries, 68 respectively. However, some vaccination data was missing for some countries and this resulted in 69 different sample sizes as reflected in the analyses. Mean vaccination coverages were correlated with 70 recovery and death rates where such vaccination data was available. Otherwise we compared country 71 death rates and recoveries according to categories of whether vaccine data was reported or not. Data 72 was also disaggregated according to the World Bank economic classification (June 2020)(14). 73

The mean death rate (±sd) from COVID-19 for 168 countries was 3.2±3.5% with a range of 0.06-29.3%, 75 while the mean recovery rate for 175 countries was 68.2±22.3%. Recoveries ranged from 8-100%. The 76

results showing a comparison of mean COVID-19 death rates between vaccinating and non-77 vaccinating countries is shown in Table 1 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 3, 2020. . https://doi.org/10.1101/2020.09.02.20186528 doi: medRxiv preprint 5 and non-vaccinating countries, with vaccinating countries showing significantly lower death rates. 80

Other vaccines did not yield significant differences between vaccinating and non-vaccinating 81 countries. 82 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 3, 2020. . https://doi.org/10.1101/2020.09.02.20186528 doi: medRxiv preprint 6 the diseases and death rates was only significant for IPV1 in high-income countries (r = -0.620, p = 93 0.042). 94

We observed that the percentage of recoveries was higher in non-vaccinating countries for the 95 diseases shown in Table 2 . 96 We also compared percent death and recovery rates according to income level of the countries. The 100 results, summarized in Table 3 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 3, 2020. . https://doi.org/10.1101/2020.09.02.20186528 doi: medRxiv preprint 7 is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprint

The copyright holder for this this version posted September 3, 2020. . https://doi.org/10.1101/2020.09.02.20186528 doi: medRxiv preprint

Correlation between 171 universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an 172 epidemiological study

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BCG vaccine protection from severe coronavirus 180 disease 2019 (COVID-19)

BCG Vaccination Protects 183 against Experimental Viral Infection in Humans through the Induction of Cytokines Associated 184 with Trained Immunity

Long-lasting effects of 186 BCG vaccination on both heterologous Th1/Th17 responses and innate trained immunity

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World Health Organization. Immunization-coverage-by-antigen-country-regional-and-global-197 trends-WUENIC-2019revision

207 Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic 208 review

We undertook an analysis of COVID-19 deaths and recoveries in light of immunization with various 117 vaccines to determine the association, if any, of vaccination in mitigating the adverse outcomes of 118 infection with the SARS CoV-2 virus. Vaccination with Hepatitis B birth dose, BCG and inactivated Polio 119 vaccine were associated with lower Covid-19 deaths. This is consistent with other reports where BCG 120 vaccination was associated with lower mortalities and severity of the disease(1, 5). We also observed 121 a weak but significant correlation suggesting that COVID-19 deaths are generally lower in countries 122where vaccination for BCG, Rubella-containing vaccines and Hepatitis B 3 rd dose are given. Moreover, 123we observed that vaccine coverage, rather than the longevity of use, has a better correlation with 124 percent deaths attributed to We note that death or recovery is also a function of the effectiveness of the health care system in any 126 country. We presumed that higher income countries would generally afford better health care 127 systems and therefore better recoveries and lower deaths. 128 129 Paradoxically, percent recoveries were significantly higher in non-vaccinating countries for 130Pneumococcal Conjugate vaccine (PCV), RotaCV and Hepatitis B-3 vaccines. We hypothesize that if 131 vaccines, as has been established, promote innate immunity (4, 7, 15, 16), then both death rates and 132 recoveries should be expected to be favourable in vaccinated individuals. However, since recovery 133 includes individuals who must have been hospitalized for symptomatic presentation or those who 134 tested positive but never needed to recover since they were asymptomatic, those with competent 135 immune systems would not be expected to be hospitalized, and would therefore be under-136represented among documented recoveries. We propose that this under-representation may account 137 for the higher recoveries in non-vaccinating countries for the specified vaccines. is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprintThe copyright holder for this this version posted September 3, 2020. Another potential limitation is the fact that the disease is still developing in many countries, so the 155 true resilience of many countries is still to be tested. It is also not clear how to interpret lower 156 recoveries especially in view of the different definitions of recovery. In Botswana, for example, 157 recovery was initially defined in the context of two successive nucleic acid tests at least twenty four 158 hours apart. The current definition now relies on the clinical manifestations and age of the infection. 159Nevertheless, the data seems to corroborate reports alluding to potential benefit of BCG of some 160 vaccines against COVID-19. 161 162

The authors declare that there are no competing interests in this study. 164

The authors confirm that the study did not require any funds. 166 . CC-BY-ND 4.0 International license It is made available under a perpetuity.is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprintThe copyright holder for this this version posted September 3, 2020. . https://doi.org/10.1101/2020.09.02.20186528 doi: medRxiv preprint 10 Data availability 167The data used in this analysis is available as a public resource from UNICEF, World Bank and 168Worldometer databases. 169

170 It is made available under a perpetuity.is the author/funder, who has granted medRxiv a license to display the preprint in (which was not certified by peer review) preprintThe copyright holder for this this version posted September 3, 2020. . https://doi.org/10.1101/2020.09.02.20186528 doi: medRxiv preprint