Wei-Ju Su

and 4 more

To the Editor:  The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARC-CoV-2) has led to an imminent need for an effective vaccination to constrain viral spread and reduce global disease morbidity and mortality. BCG, a live attenuated vaccine against tuberculosis, was demonstrated to have a non-specific immunomodulatory effects, by training the innate immune system to generate memory, which aided the host in fighting a wide range of viral infections in subsequent years.1 BCG was reported to reduce viremia, respiratory tract infections, and neonatal mortality,1 but it was not tested effectively in a recent, large randomized trial.2 Whether BCG vaccination could have a beneficial effect against COVID-19 is under debate. In a recent PNAS article, Escobar et al. found an inverse relation between the BCG index and COVID-19 mortality in socially similar European countries.3 Several ecological studies did suggest the potential protective effect of the universal BCG vaccination program on reducing COVID-19 mortality;4-6 they also suggested that different BCG strains might vary in their protective ability.7 In contrast, one study in Israel found no difference in the SARS-CoV-2-positive rate between individuals born during the period of mandatory BCG vaccinations and those born outside that period.8 All these studies analyzed aggregated data at the population level without directly comparing individuals that did to those that did not receive BCG vaccinations. By linking with the web-based National Immunization Information System (NIIS) in Taiwan, here we describe the clinical severity in confirmed COVID-19 cases between Jan 21 and May 5, 2020 and their individual BCG vaccination records.   Taiwan has continued a nationwide neonatal BCG vaccination program since 1965. Initially, neonates were vaccinated with the Pasteur-1173 P2 strain, but in 1979, vaccinations shifted to the Tokyo-172 strain. The BCG vaccine coverage rate increased to 87% in 1975,9 and it has remained at 95.7%–98.8% since 1996. Electronic vaccine records in NIIS were compiled for individuals born as early as the 1980s. Taiwan Centers for Disease Control surveyed the NIIS database and found that the completeness of public-funded childhood immunization electronic records was above 90% for individuals born after 1996.  Through the National Notifiable Disease Surveillance System in Taiwan, COVID-19 was confirmed in 416 Taiwanese patients (median age: 36.3 years; mean: 40.2 years, range: 4-88 years; with 212 [51.0%] females) between Jan 21 and May 5, 2020. The diagnoses were based on positive SARC-CoV-2 RNA identification in real-time reverse transcriptase-polymerase chain reactions (RT-PCRs). Among them, 366 (88.0%) had imported the disease from other regions. These patients reported travel to the following regions within 14 days of disease onset: 184 (50.3%) to European regions, 91 (24.9%) to American regions, 26 (7.1%) to Western Pacific regions, 11 (3.0%) to Eastern Mediterranean regions, 9 (2.5%) to South-East Asia regions, 4 (1.1%) to African regions, and 41 (11.2%) to at least two of the regions mentioned.   The highest rate of COVID-19 cases occurred among individuals aged 18–24 years (56.3 per million), followed by individuals aged 25–33 years (38.1 per million), and individuals aged 34–41 (14.4 per million). According to the clinical syndrome associated with COVID-19, defined by the World Health Organization,10 the clinical severity of these COVID-19 cases varied by age (Table 1). Approximately 80% of individuals aged 18–41 years with COVID-19 experienced a mild illness (including asymptomatic infections). In contrast, among individuals aged 42–54 and ≥ 55 years, 43.1% and 38.9%, respectively, had a mild illness, up to 2% and 16%, respectively, had severe pneumonia, and 10% in both age groups had acute respiratory syndrome. Among 9 children (<18 years) with COVID-19, three had pneumonia. Of the 416 confirmed COVID-19 cases, 126 (30.3%) were born after 1996 (with onset age of 24 years or younger). According to the clinical syndrome associated with COVID-19, defined by the World Health Organization, we examined the relationship between COVID-19 severity and BCG vaccination status among individuals aged 4–24 years (Table 2). Among 123 individuals that received neonatal BCG vaccinations, 19 (15.4%) had pneumonia (moderate disease), 3 (2.4%) had severe pneumonia (severe disease, including one acquired intensive care unit admission), and none died. In contrast, all three individuals in this age group that did not receive neonatal BCG vaccinations experienced asymptomatic infection or mild illness. In the 25–33 age group, pneumonia or severe pneumonia occurred in 2 of the 33 (6.1%) patients with neonatal BCG vaccination records, compared to 14 of the 76 (18.4%) patients without neonatal BCG vaccination records (Table 2).   Our data suggested that, compared to individuals that did not have BCG vaccination records at birth, young adults aged 4–24 years that received the Tokyo-172 BCG vaccination at birth did not appeared to experience lower COVID-19 severity. The difference in COVID-19 morbidity and mortality in the young population between Taiwan that with current universal neonatal BCG vaccination program and the US that never having such program remains to be discovered. According to the recent reports, the hospitalization, ICU admission, and case-fatality rate in the US was 14.3-20.8%, 2.0-4.2%, 0.1-0.2% for patients aged 20-44 years,11 and 5.7-20%, 0.58-2.0%, 0% for those aged <18 years,12 respectively. Of note, these data should be interpreted cautiously because the numbers of cases (the stage and the size of COVID-19 epidemic) were small. We propose countries with available BCG records to conduct pooled analysis to provide in-time information on the presence or absence of BCG cross-protection from severe COVID-19 in different age groups.