key: cord-0916553-ucwnq7hh authors: Asahara, Masakazu title: The effect of BCG vaccination on COVID-19 examined by a statistical approach: no positive results from the Diamond Princess and cross-national differences previously reported by world-wide comparisons are flawed in several ways date: 2020-04-22 journal: nan DOI: 10.1101/2020.04.17.20068601 sha: ba30cb3051316d70b0b8a60667d07a64bfa6d6b8 doc_id: 916553 cord_uid: ucwnq7hh Recently, the controversial hypothesis that BCG (Bacillus Calmette-Guerin) vaccination reduces infection or severity of COVID-19 has been proposed. The present study examined this hypothesis using statistical approaches based on the public data. Three approaches were utilized: 1) comparing the infection and mortality ratio of people on the cruise ship Diamond Princess, 2) comparing the number of mortalities among nations, and 3) comparing the maximum daily increase rate of total mortalities among nations. The result of 1) showed that there is no significant difference in infection per person onboard and mortality-infection between Japanese citizens vs. other nationalities and BCG obligatory nations vs. non-BCG obligatory nations on the Diamond Princess. The result of 2) showed that the number of mortalities among nations is similar to the previous studies, but this analysis also considered the timing of COVID-19 arrival in each nation. After correcting for arrival time, previously reported effect of BCG vaccination on decreasing total mortality disappeared. This is because nations that lack BCG vaccination are concentrated in Western Europe, which is near an epicenter of COVID-19. Therefore some previous reports are now considered to be affected by this artifact; the result may have been flawed by on-land dispersal from an epicenter. However, some results showed weakly significant differences in the number of deaths at a particular time among BCG obligatory and non-BCG nations (especially the use of Japanese BCG strain Tokyo 172). However, these results are affected by the results of three countries and the effect of BCG vaccination remains inconclusive. The result of 3) showed that the maximum daily increasing rate in death among nations showed no significant difference among BCG vaccination policies. In the present study, although some results showed statistically significant differences among BCG vaccination policies, they may be affected by the impact of various other factors, such as national infection-control policies, social distancing, behavioral changes of people, possible previous local epidemics of closely related viruses, or inter-population differences in ACE2 or other genetic polymorphism. Further research is needed to better understand the underlying cause of the observed differences in infection and mortality of the disease among nations. Nevertheless, our results show that the effect of BCG vaccination, if any, can be masked by many other factors. Therefore, the possible effect might be relatively small. In fact, in Japan, where almost all citizens have been vaccinated, COVID-19 cases are constantly increasing. Given the importance of peoples behavior in preventing viral propagation, the spread of optimism triggered by this hypothesis would be harmful to BCG vaccination nations. T h e e f f e c t o f B C G v a c c i n a t i o n o n C O V I D -1 9 e x a m i n e d b y a s t a t i s t i c a l a p p r o a c h : n o p o s i t i v e r e s u l t s f r o m t h e D i a m o n d P r i n c e s s a n d c r o s s -n a t n a t i o n s s h o w e d n o s i g n i f i c a n t d i f f e r e n c e a m o n g B C G v a c c i n a t i o n p o l i c i e s . I n t h e p r e s e n t s t u d y , a l t h o u g h s o m e r e s u l t s s h o w e d s t a t i s t i c a l l y s i g n i f i c a n I n t r o d u c t i o n I n A p r i l 2 0 2 0 , t h e g l o b a l p a n d e m i c o f c o r o n a v i r u s d i s e a s e -2 0 1 9 ( C O V I D -1 W e s t e r n E u r o p e , w h i c h i s n e a r a C O V I D -1 9 e p i c e n t e r . T h i s s h o u l d a f f e c t t h e c o n c l u s i o n s o f p r e v i o u s s t u d i e s . T h e r e f o r e , t h e p r e s e n t s t u d y a t t e m p t e d t o e x a m i n e t h e e f f e c t o f B C G v a c c i n a t i o n w h i l e a c c o u n t i n g f o r t h e s e b i a s e s . T h r e e a p p r o a c h e s w e r e u s e d i n t h e p r e s e n t s t u d y . T h e f i r s t a p p r o a c h i s a t e s t i n t h e c r u i s e s h i p D i a m o n d P r i n c e s s . I n t h i s s h i p , m o s t p a t i e n t s w e r e i n f e c t e d b e f o r e t h e y w e r e a w a r e t h a t t h e d i s e a s e w a s s p r e a d i n g i n t h e s h i p . T h e r e f o r e , t h e c u l t u r a l e f f e c t o f c o u n t r i e s ( s u c h a s w e a r i n g m a s k s ) o r n a t i o n a l p o l i c y ( s u c h a s t h e " c l u s t e r b u s t e r " p o l i c y i n J a p a n ) c a n b e e x c l u d e d . T h e s t r a i n o f v i r u s o n t h e s h i p i s t h e s a m e , a n d t h e s p r e a d o c c u r r e d s i m u l t a n e o u s l y o n b o a r d ( S e k i z u k a e t a l . 2 0 2 0 ) . T h e s e c o n d a p p r o a c h i s a s i m i l a r c o m p a r i s o n a s i n m a n y p r e v i o u s s t u d i e s ( e . g . M i l l e r e t a l . 2 0 2 0 ; S a l a a n d M i y a k a w a 2 0 2 0 ) . T h a t i s , t h e n u m b e r o f m o r t a l i t i e s i n e a c h n a t i o n w a s c o m p a r e d , b u t w i t h c o n s i d e r a t i o n f o r t h e t i m i n g o f d i s e a s e a r r i v a l . T h e t h i r d a p p r o a c h i s a l s o s i m i l a r t o a p r e v i o u s s t u d y ( A k i y a m a a n d I s h i d a 2 0 2 0 ) . T h a t i s , t h e r a t e o f i n c r e a s e o f t h e n u m b e r o f m o r t a l i t i e s i n e a c h n a t i o n w a s c o m p a r e d . M a t e r i a l s a n d M e t h o d s D a t a w a s o b t a i n e d f r o m p r e v i o u s p u b l i c a t i o n s o r p u b l i c d a t a b a s e s . T h e n u m b e r o f c a s e s , d e a t h s , a n d p a s s e n g e r s ' n a t i o n a l i t y o n t h e D i a m o n d p r i n c e s s w a s o b t a i n e d f r o m p u b l i c d a t a ( M i n i s t r y o f H e a l t h , L a b o u r a n d W e l f a r e , J a p a n , 2 0 2 0 a ; b ) . a t i o n a l i t i e s o f d e a d p a s s e n g e r s w e r e o b t a i n e d f r o m e a c h n e w s r e p o r t . D a t a o n c a s e s a n d m o r t a l i t y f r o m e a c h n a t i o n w a s o b t a i n e d f r o m a c a s e , t h i s a l i g n m e n t i s c o n s i d e r e d b e t t e r b e c a u s e t h e s p e c i f i c n u m b e r o f t h e c a s e d e p e n d s o n t h e n a t i o n a l p o l i c y o f e x a m i n a t i o n . I n a d d i t i o n , t h e p r e s e n t s t u d y f o c u s e d o n t h e t o t a l n u m b e r o f d e a t h s i n e a c h n a t i o n , r a t h e r t h a n d e a t h p e r p o p u l a t i o n , b e c a u s e t h e p a n d e m i c w a s s e v e r e i n p a r t i c u l a r c i t i e s o r p a r t i c u l a r a r e a s . M o r e o v e r , n a t i o n a l p o l i t i c a l d e c i s i o n s t o p r e v e n t d i s e a s e s p r e a d , w h i c h i s o n e o f t h e m o s t i m p o r t a n t f a c t o r s o f d i s e a s e s p r e a d , s h o u l d b e a f f e c t e d b y t h e t o t a l n u m b e r o f v i c t i m s . T h e r e f o r e , a l i g n i n g t o t h e t o t a l n a t i o n a l p o p u l a t i o n i s i r r e l e v a n t . M o r e o v e r , a l m o s t a l l p e o p l e a r e s t i l l c o n s i d e r e d s u s c e p t i b l e t o t h e d i s e a s e . I n s o m e n a t i o n s , s u c h a s C h i n a , t h e i n c r e a . 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) . 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 April 22, 2020. . 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 April 22, 2020. . 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 April 22, 2020. . 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 April 22, 2020. . s e i s a k u n i t s u i t e / b u n y a / 0 0 0 0 1 6 4 7 0 8 _ 0 0 0 0 1 . h t m l M i n i s t r y o f H e a l t h , L a b o u r a n d W e l f a r e , J a p a n , 2 0 2 0 b . D i a m o n d P r i n c e s s C a s e s . ( a c c e s s e d i n 2 0 2 . 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 April 22, 2020 . . https://doi.org/10.1101 /2020 e c o l o g i c a l d i v e r s i t y o f b a t v i r u s e s a n d t h e b a t o r i g i n o f e m e r g i n g i n f e c t i o u s d i s e a s e s . T h e I S M E J o u r n a l 1 0 : 6 0 9 -6 2 . 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 April 22, 2020 . . https://doi.org/10.1101 /2020 . 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 April 22, 2020 . . https://doi.org/10.1101 /2020 *There are still 16 people in hospital whose nationality is undisclosed Table 1 . Case fatality ratio between nationality of different BCG vaccination policies in the Diamond Princess (April 11, 2020) . 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 April 22, 2020. . *There are still 16 people in hospital whose nationality is undisclosed Table 2 . Infection and mortality ratio between citizens of Japan and other countries in the Diamond Princess (April 11, 2020) . 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 April 22, 2020 April 22, . . https://doi.org/10.1101 April 22, /2020 doi: medRxiv preprint Table 3 . The result of general linear model testing for the effect of BCG vaccination and other factors using all available nations aroud the world ( Fig. 1 and 2 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 April 22, 2020. (Fig. 4) Log Total Death = BCG polocy + Date 5th death . 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 April 22, 2020. 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 April 22, 2020. . 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 April 22, 2020. . 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 April 22, 2020 . . https://doi.org/10.1101 /2020 . 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 April 22, 2020. . 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 April 22, 2020. Fig. 6 . Box plots of maximum increase rate per day (two week average). Nations where deaths are more than 100 and 25 were separately illustrated. Boxes indicate quartiles, central-lateral bars indicate medians, vertical bars indicate the range of the specimens, and asterisks indicate outliers. The increase rate seems to higher in BCG -nations. However, only one pair was weakly statistically significant, but most are not (ANOVA/ Tukey' s test). . 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 April 22, 2020. 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 April 22, 2020 . . https://doi.org/10.1101 /2020 Although the increase rate in Iraq, Korea, and Japan seem to low