key: cord-298867-hzshnq7b
authors: Raham, T. F.
title: Impact of Duration of Cessation of Mass BCG Vaccination Programs on Covid -19 Mortality
date: 2020-08-23
journal: nan
DOI: 10.1101/2020.08.20.20178889
sha: 
doc_id: 298867
cord_uid: hzshnq7b

Back ground: BCG have heterogeneous immunity to certain pathogens other than Mycobacterium tuberculosis effect. At early times during COVID-19 pandemic heterogeneous immunity towards (SARS-CoV-2), was hypothesized and statistical correlation between of BCG vaccination practices and COVID-19 mortality variances among countries was statistically proved . These studies was criticized because of low evidence of such studies and possible confounding factors. For that reason this study was designed to look for impact of duration of cessation of BCG programs on Covid-19 mortality looking for the hypotheses by different design and looking forward to support previous studies. Methods: Total number of studied group is 14 countries which has stopped BCG vaccination programs. Through applying stem-leaf plot for exploring data screening behavior concerning Covid-19 Mortality for obsolescence duration of cessation of mass BCG vaccination programs, as well as (nonlinear regression of compound model) for predicted shape behavior for that group. Results: Slope value shows highly significant effectiveness of obsolescence of cessation of mass BCG vaccination programs on Covid -19 mortality at P-value<0.000. Obsolescence of duration of cessation of mass BCG vaccination programs has strongly negatively associated with Covid-19 mortality in countries which stopped BCG vaccination programs. Conclusion: The longer the cessation duration of BCG programs, the higher the Covid-19 mortality is, and vice versa.

Epidemiological and immunologic studies have shown reductions in morbidity and mortality following BCG immunizations in third world countries, suggesting that BCG may have some role in heterologous immunity to other pathogens 1 The biological substrate of these effects is mediated partly by heterologous effects on adaptive immunity, but also on the potentiation of innate immune responses through 'trained immunity 3 . The term heterologous immunity refers to the immunity that can develop to one pathogen after a host has had exposure to non-identical pathogens 4 BCG vaccination significantly increases the secretion of pro-inflammatory cytokines, such as IL-1β and IL-6, which has been shown to play a vital role in antiviral immunity 5 A rapid review 9 and WHO brief 11 on 12 April 2020 evaluate the current evidence about the protective effects of BCG vaccine against acute respiratory infections and COVID-19. Although some have significant correlation brief states "WHO does not recommend BCG vaccination for the prevention of COVID-19"claiming that evidence is not strong enough yet.

Although heterogeneous immunity is not effective as homologous immunity to a specific pathogen which will usually develop a very strong resistance to re-infection with the same pathogen 12 ,interests in heterogeneous protection is of great concern in SARS-COV-2 infection as far as there is no available vaccine for COVID -19 yet. Criticized studies hypothesized this theory and share the design of testing the BCG vaccination practices against morbidity and moratlity 9 . By testing the duration of cessation of BCG vaccination against COVID-19 mortality in this work , we are looking for the link by different design. The hypothesis in this study is the waning effect of vaccination as far as, the heterogeneous immunity waned with time 13 . So the primary aim of this study is supporting for previous studies through handling the question of immunity that's BCG thought to be produced against (SARS-. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted August 23, 2020. . https://doi.org/10.1101/2020.08.20.20178889 doi: medRxiv preprint CoV-2) by different way that is the cessation duration of BCG programs in countries which stopped BCG vaccinations programs.

Data regarding time of BCG cessation versus Covid-19 mortality is subjected to be tested. Information on past BCG vaccination and cessation dates were collected from countries by data abstracted from published papers, reports, and available government policy documents retrieved through literature searches on PubMed and via the World Wide Web furthermore, we used immunization data available from the WHO-UNICEF estimates of BCG coverage site: https://apps.who.int/immunization_monitoring/globalsummary/timeseries/tswuc of national immunization coverage, and WHO UNICEF review overagebcg.html at site immunization surveillance, assesment and monitoring data and 2018 -1980 https://www.who.int/immunization/monitoring_surveillance/data/afg.pdf : It was not appropriate or possible to involve patients or the public in this work given that we used general practice level summated data and related publically published mortality statistics and national BCG protocols. 

Obsolescence of cessation of mass country . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 23, 2020. In addition to that, stem-leaf plot was used for exploring data screening behavior concerning Covid-19 Mortality with obsolescence of cessation of mass BCG vaccination in countries previously given the BCG vaccine which are redistributed in three groups intervals. All statistical operations were performed through using the ready-made statistical package SPSS, version 22. 

Linear Model whose equation is Y = b0 + (b1 * t).

Model whose equation is Y = b0 + (b1 * Ln (t)).

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 23, 2020. . https://doi.org/10.1101/2020.08.20.20178889 doi: medRxiv preprint Inverse Model whose equation is Y = b0 + (b1 / t).

Model whose equation is Y = b0 + (b1 * t) + (b2 * t**2).

Model whose equation is Y = b0 * (t**b1) or Ln (Y) = Ln (b0) + (b1 * Ln(t)).

Model whose equation is Y = b0 * (b1**t) or Ln(Y) = Ln(b0) + (Ln(b1) * t).

Model whose equation is Y = e**(b0 + (b1/t)) or Ln(Y) = b0 + (b1/t).

Model whose equation is Y = 1 / (1/u + (b0 * (b1**t))) or Ln(1/y-1/u)= Ln (b0) + (Ln(b1)*t) Exponential Model whose equation is Y = e**(b0 + (b1 * t)) or Ln(Y) = b0 + (b1 * t).

Model whose equation is Y = b0 * (e**(b1 * t)) or Ln(Y) = Ln(b0) + (b1 * t). them. In addition to that, the observations that increased in more than three degree of standard values from the two sides would be assigned by a star and known as an outlier value.

. CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 23, 2020. . https://doi.org/10.1101/2020.08.20.20178889 doi: medRxiv preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 23, 2020. . be an expected on Covid -19 mortality/million with the peak effectiveness of using vaccine at the earliest possible period, and rather than no significant Pvalue >0.05 was accounted, since probability level of significance simply stating not achieved. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 23, 2020. . https://doi.org/10.1101/2020.08.20.20178889 doi: medRxiv preprint

Results reflect statistical correlation between BCG duration of obsolesce of cessation (when cessation time is diminished or degenerated) and COVID-19 mortality and being strongly negatively associated (Fig.1, Fig.2, table3) . This association reflects the shorter cessation period of BCG vaccination the lesser COVID-19 mortality and vice versa. Looking for duration of cessation of BCG vaccination program as factor is a new idea up to my knowledge to be tested in relation to COVID-19 mortality supporting the hypotheses of effectiveness of BCG vaccinations programs in prevention of COVID-19 mortality. Previous studies regarding BCG effectiveness where criticized by possibility of significant bias from many confounders . Possible confounders : differences in national demographics and disease burden, testing rates for COVID-19 virus infections, and the stage of the pandemic in each country9. In this study although above confounders cannot excluded but the design of the study is different from other studies . The influence of time proved in this study is of concern since previously criticized studies prove significant associations results with practices, results of this study and previous studies consolidate each other through different study designs . In one study done before there was a positive significant correlation (ρ=0.54, p=0.02, linear correlation) between the year of the establishment of universal BCG vaccination and the mortality rate. This study did not assess the impact of cessation but the time of establishment of vaccination programs and includes both groups of countries which continue and not continue the vaccination programs ,although the design is different again her, but similar finding consolidates evidence to each other 10 . Another more recent study shows highly significant negative association between prevalence of TB and covid-19 mortality which furtherly support such hypothesis regarding heterogeneous immunity of Mycobacterium through latent TB infections which it's prevalence is proportional to TB prevalence 14 .

Highly significant association in this study support the hypotheses already raised about beneficial effect of vaccination and hence impact of its cessation. The theoretical background for this association is protection role of heterogeneous immunity produced by BCG vaccine. As far as the duration of cessation of vaccination in this study have impact on mortality , its results might reflects the waning effect of heterogeneous immunity but still this finding should be confirmed by control clinical studies and immunological studies. For such clinical studies we need more time to wait to see such studies and this give importance to do such studies in this time. While this study states that duration of cessation of BCG programs have impact on COVID-19 mortality / million populations inhabitant explains more possible factor in variances in COVID-19 . CC-BY-NC-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted August 23, 2020. . https://doi.org/10.1101/2020.08.20.20178889 doi: medRxiv preprint mortality through different countries in one hand and strengthen the evidence for early intervention at this critical time in another hand. Conclusion: Duration of cessation of BCG vaccination have significant effect on mortality due to Covid-19 and this study supports the evidence of effect of BCG vaccination in prevention of COVID -19 mortality. Recommendations: Decisions on BCG vaccination program cessation might be en reconsidered.

Ethical permission is not necessary as this study analyzed publically published data and patients were not involved.

There is no conflict of interest.

There is no funding received. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review)

The copyright holder for this preprint this version posted August 23, 2020. . https://doi.org/10.1101/2020.08.20.20178889 doi: medRxiv preprint

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Technology college, Baghdad-Iraq, for his assistance and supported in data analysis, interpretations of finding results, and revise and display the paper.