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Table.  Results of SARS-CoV-2 PCR Testing by Age Group
Results of SARS-CoV-2 PCR Testing by Age Group
1.
Miller  A, Reandelar  MJ, Fasciglione  K,  et al. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. medRxiv. Preprint posted March 28, 2020. doi:10.1101/2020.03.24.20042937
2.
Berg  MK, Yu  Q, Salvador  CE,  et al. Mandated bacillus Calmette-Guérin (BCG) vaccination predicts flattened curves for the spread of COVID-19. medRxiv. Preprint posted May 4, 2020. doi:10.1101/2020.04.05.20054163
3.
Hollm-Delgado  MG, Stuart  EA, Black  RE.  Acute lower respiratory infection among bacille Calmette-Guérin (BCG)-vaccinated children.   Pediatrics. 2014;133(1):e73-e81. doi:10.1542/peds.2013-2218PubMedGoogle ScholarCrossref
4.
Leentjens  J, Kox  M, Stokman  R,  et al.  BCG vaccination enhances the immunogenicity of subsequent influenza vaccination in healthy volunteers: a randomized, placebo-controlled pilot study.   J Infect Dis. 2015;212(12):1930-1938. doi:10.1093/infdis/jiv332PubMedGoogle ScholarCrossref
5.
Netea  MG, van Crevel  R.  BCG-induced protection: effects on innate immune memory.   Semin Immunol. 2014;26(6):512-517. doi:10.1016/j.smim.2014.09.006PubMedGoogle ScholarCrossref
6.
Israel Central Bureau of Statistics. Jews by continent of origin, sex and age. Accessed April 25, 2020. https://www.cbs.gov.il/en/publications/Pages/2018/Immigration-Statistical-Abstract-of-%20Israel-2018-No-69.aspx
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    8 Comments for this article
    EXPAND ALL
    This is Not the Question Being Asked in Trials of BCG for COVID-19
    Nigel Curtis, MD PhD | University Hospital
    We do not expect BCG vaccine given many years earlier to protect against COVID19. Trained immunity induced by BCG might not be long-lasting and is likely abrogated by other intervening vaccines. See comments at https://twitter.com/nigeltwitt/status/1258561482280759296
    CONFLICT OF INTEREST: Chief Principal Investigator of BRACE trial of BCG vaccination for COVID-19
    Age Group 20-29 Without BCG Has More Cases Than Any Others
    Tsuyoshi Miyakawa, Ph. D. | Fujita Health University
    Here are my concerns on this paper.

    1. The absolute number of cases in age group 20-29 without BCG is greater than any other age groups in Israel based on data from the Israel Science and Technology Directory (https://www.science.co.il/medical/coronavirus/Distribution-age.php)

    When adjusted by population of each age group, the number of cases per 10K pop of each age group is
    70, age group 0-9
    208, 10-19
    442, 20-29
    265, 30-39
    294, 40-49
    375, 50-59
    321, 60-69
    358, 70-79
    483,  80+

    The number of cases of age group 20-29 (442 per 10k pop of this age group)
    who are supposed to lack BCG-vaccination is still substantially higher than those of other groups who are supposed to have been vaccinated.

    In other words, the authors picked up and showed the data from narrow age range groups that do not have differences. I believe they also looked at the data of 20-29 but did not show this unvaccinated age group that has greater number of cases than most of other groups that were vaccinated.

    2. If any protective effect of BCG exists, herd immunity is also expected to be seen. Such herd immunity would obscure differences between age groups. Also, it is suggested that other vaccines, such as the ones for Measles and Rubella, may also have protective effect (Saad and Elsalamony, 2020), which may also obscure age group differences, if any. I suppose this kind of analyses would not be able to test the hypothesis well. This study might be an example of the idea,“Absence of evidence is not an evidence of absence."

    3. The BCG strain may matter. In Israel, BCG Glaxo seems to have been used, which has large genomic deletions and is hypothesized to be among “weak” ones, which are commonly used in high COVID-19 burden countries.

    4. The number of cases may not be a reliable index for assessing the potential effect of BCG. This could be affected by strategy of testing. The number of death would be a better index.

    5. Since the absolute number of cases is quite small (around 300-400), it can be largely affected by “cluster” of infections easily. A cluster can be more than 100 cases.This kind of noisy data of just 3 years slice taken from 1 country sample may not be reliable to draw any conclusions.

    While the authors note that the BCG coverage was over 90%, according to WHO website, BCG coverage in Israel was only 75 and 70% in 1980 and 1981, respectively. 
    https://apps.who.int/gho/data/node.main.A830?lang=en

    What was the source of the BCG coverage data the authors used?
    CONFLICT OF INTEREST: None Reported
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    Study Design Concerns
    Ana Vasileva, PhD | SUNY Downstate Medical Center, New York, USA
    I agree with all of the points brought forward by Dr. Miyakawa.

    In addition, while this study is intended to compare large populations without confounders, there are a couple that I can think of, which have not been taken into account.

    1. The single dose of BCG vaccine administered at birth provides at most 15 years of immunity. The cohort of individuals selected as immunized between 1979-1981 likely did not receive a booster to extend the effect beyond this period.

    2. The cohort of people born between 1983-1985 would have included at least 15 %
    of vaccinated individuals, who were the children of immigrants from the former Soviet Union where BCG vaccination and re-vaccination was mandatory.

    Finally, a country where a study like this (the same age group or anyone born before 1985) will most likely have legitimate outcome and conclusion is Germany. West Germany ceased their BCG vaccination policy long before East Germany.
    CONFLICT OF INTEREST: None Reported
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    BCG requires further study.
    Gary Ordog, MD, DABMT, DABEM | County of Los Angeles, Department of Health Services, Physician Specialist (retired)
    Thank you to the authors for a first attempt at answering the BCG question. Unfortunately, more research is required before we know an answer. I would not expect that the BCG would alter the external viral contamination rate. This is a novel virus for which the body should have no pre-existing immune response. The BCG was not intended for this new virus. The theory is that the BCG may "boost" the immune system to better handle the virus, once exposed. The patients did not have time to mount an immune response, because they had recently been exposed, and were presumably newly symptomatic, prompting the viral test. Also, presumably, at a later date, the patients will develop antibodies, including IgE in their nasal secretions to eliminate the viral RNA your tests picked up. So the results are to be expected, but really don't answer the question of any benefit of BCG in COVID-19. As far as method, the groups are not standardized, the ages are different, vaccination figures don't agree with others, and for some groups the vaccination rate is completely uncertain. But thank you for a start. We need more research to answer the question.
    CONFLICT OF INTEREST: None Reported
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    Misleading Title
    Qunfeng Dong, Ph.D. | Loyola University Chicago
    As the authors mentioned at the end of their discussion, their results should not be generalized to the population since the persons tested in this study were preselected based on reported symptoms. Therefore, their result only indicates that, conditioned on having COVID-19 symptoms, people with and without BCG vaccination in their childhood have similar SARS-CoV-2 positive rates. This result does not directly test the unconditional hypothesis that BCG vaccination in childhood has a protective effect against COVID-19 in adulthood. Therefore, I wish that the current title of this paper could be changed to "SARS-CoV-2 Rates in BCG-Vaccinated and Unvaccinated Young Adults with COVID-19 Symptoms" to avoid any potential misunderstanding.
    CONFLICT OF INTEREST: None Reported
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    BCG has potential cross immunity
    Dr Mubarak M Khan, MBBS, DLO, DNB(ENT) | Sushrut ENT Hospital & Dr Khan’s Research Centre, Pune India
    BCG is a live attenuated tuberculosis vaccine that has the ability to induce non-specific cross-protection against pathogens that might be unrelated to the target disease. Innate immune cells, including monocytes and natural killer (NK) cells, contribute to this non-specific immune protection in a way that is independent of memory T or B cells. The duration of immunity is somewhere between 15 and 60 years post-immunization in different trials. This nonspecific immunity can be boosted by a second dose of BCG vaccine and repeating it every 15 years to induce non-specific cross-protection. With the health menace created by Sars Cov 2 and previously by Sars Cov 1 and MERS (and many more deadly viral infections in the future), finding a vaccine for the viral infection during the pandemic is a time-consuming process, when we are witnessing the viral wrath taking a toll of human lives. So why not just revive the time-tested vaccines which are providing the cross immunity during the pandemic? It’s just a scientific clinical decision whether to incorporate the second dose of such established vaccine or not. Meanwhile this will not only buy the time (to develop the specific vaccine) to combat the severity of the disease in the form of increased immunity, but will also create reliable data with prospective research. Why shouldn’t this be the norm to be prepared for the future pandemics instead of being rattled by the new virus without treatment and vaccine? We firmly believe that in the future, the cross immunity created by existing vaccines with multiple booster doses (that needs to be decided by authorities with multiple trials) will save the public from many health hazards. When exorbitant funds are involved in developing the vaccine for the new virus (which is a need of the hour), these randomised trials of revaccinations can be carried out at a much more meagre amount and without any side effects. Giving the booster doses depends just on political will and the consensus of the clinicians and developing a strong unanimous policies for future.

    Sincere Regards,
    Dr Mubarak M. Khan (MBBS, DLO, DNB ENT)
    Consultant, Director
    Dr. Sapna R. Parab (MBBS, MS, DNB ENT)
    Consultant and Ex Prof and Head ENT,
    Sushrut ENT Hospital, Talegaon D, Pune, India
    CONFLICT OF INTEREST: None Reported
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    Covid-19 Severity and Its Relation to Live Vaccines
    Rainer Spiegel, MD PhD | Anesthesiology and Intensive Care, BG Trauma Center, University of Tuebingen, Germany
    In their Research Letter, Hamiel and colleagues provide results on SARS-CoV-2 numbers among adults who were formerly BCG-vaccinated as newborn babies. They compared those numbers with adults who were not BCG-vaccinated. It is a highly interesting finding that formerly BCG-vaccinated adults had a similar SARS-CoV2 rate as those without a BCG-vaccination. What makes this comparison strong is that the cohort consisted of similar age groups. In addition, Hamiel and colleagues thoughtfully deduced that the limited number of severe cases does not permit a conclusion about the relation between former BCG-vaccination and the severity of the disease.

    I wonder whether
    it would be a good idea to extend this study by stratifying by recency of BCG-vaccination (see Nigel Curtis’ and Ana Vasileva’s comments) and by including other live vaccines. When it comes to the severity of the disease, it might matter how many other live vaccines a person has received up to the date of infection with SARS-CoV-2 and how recent those vaccinations were.
    CONFLICT OF INTEREST: I have a limited number of stocks of a respirator/ventilator company.
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    Misleading Results?
    Jacques Pepin, MD | Universite de Sherbrooke, Canada
    Whether BCG provides some degree of protection against SARS-CoV-2, through trained immunity, is an important question. But apart from the limitations mentioned by the authors themselves and some of the commentators here, there are other methodological issues.

    First, the authors allege that >90% of Israeli citizens born in 1979-1981 received BCG, and then use 100% coverage for their ecological study. However, the World Health Organization and UNICEF report that only 75% and 70% of children born in Israel in 1980 and 1981 did receive BCG (1). Second, it seems unlikely that, in 1979-1981, non-vaccination was randomly distributed within the
    Israeli population. Haredi (Ultra-Orthodox) communities had low vaccination coverage (2), and were probably overrepresented among the unvaccinated. They also happen to be the hardest hit for COVID-19, such that the Israeli army had to cordon off the Bnei Brak city near Tel Aviv, where 2901 cases occurred in a population of 200,000. The Haredim, which make up 13% of Israel’s population, represent 40-50% of COVID-19 cases nationally, and 75% in Jerusalem (3).

    Thus between 25% and 30% of the 1979-1981 birth cohorts were misclassified for their exposure to BCG, and for some of them, the unvaccinated Haredim, this was related to the probability of developing COVID-19 forty years later. This represents such a heavy differential misclassification of exposure bias that the results presented are misleading.

    Additional studies are needed. A reliable measure of exposure to BCG (immunization cards, registry, and/or presence of BCG scar) is essential. Interpretation of these studies will need to take into consideration genetic variations in BCG strains across the world.

    With regard to the duration of a putative non-specific protection provided by BCG against SARS-CoV-2, if it exists, nobody knows the answer. It may be short, it may be very long. The non-specific protection conferred by BCG in infancy against respiratory infections persists into adulthood. BCG-induced protection against tuberculosis lasts for at least 30 years, and perhaps up to 60 years, and we now know that some of the protection conferred by BCG against Mycobacterium tuberculosis develops through trained innate immunity. Let’s keep an open mind.

    REFERENCES

    1-World Health Organization. WHO-UNICEF estimates of BCG coverage.https://apps.who.int/immunization_monitoring/globalsummary/timeseries/tswucoveragebcg.html. Accessed May 15, 2020.
    2-Muhsen K, El-Hai RA, Amit-Aharon A et al. Risk factors of underutilization of childhood immunizations in ultraorthodox Jewish communities in Israel despite high access to health care services. Vaccine. 2012;30:2109-2115.
    3-Wikipedia. COVID-19 pandemic in Israel. https://en.wikipedia.org/wiki/COVID-19_pandemic_in_Israel Accessed May 15, 2020
    CONFLICT OF INTEREST: None Reported
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    Research Letter
    May 13, 2020

    SARS-CoV-2 Rates in BCG-Vaccinated and Unvaccinated Young Adults

    Author Affiliations
    • 1The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
    JAMA. Published online May 13, 2020. doi:10.1001/jama.2020.8189

    Confirmed cases of coronavirus disease 2019 (COVID-19) and case-fatality rates vary among countries. One reason could be national policies regarding childhood BCG vaccination, with fewer confirmed cases and a lower death toll reported in countries with vs without universal BCG vaccine coverage.1,2 Comparing outbreak characteristics between countries is influenced by potential confounders such as different phases of outbreak, mean age of affected population, management of the pandemic, amount of tests being administered, definitions of COVID-19–related deaths, or underreporting.

    The BCG vaccine was routinely administered to all newborns in Israel as part of the national immunization program between 1955 and 1982. Overall, the vaccine acceptance rate in Israel is high, with greater than 90% coverage. Since 1982, the vaccine has been administered only to immigrants from countries with high prevalence of tuberculosis. This change allowed comparison of infection rates and proportions with severe COVID-19 disease in 2 similar populations with differing BCG status: individuals born during the 3 years before and 3 years after cessation of the universal BCG vaccine program.

    Methods

    The current policy of the Israeli Ministry of Health is to test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in every patient with symptoms that could be compatible with COVID-19 (cough, dyspnea, fever). Nasopharyngeal swabs were tested by real-time reverse transcriptase–polymerase chain reaction in approved laboratories between March 1 and April 5, 2020. Only 1 test per patient was included. Results were stratified by birth year. Population data for specific birth years were obtained from the national Central Bureau of Statistics. χ2 Tests were used to compare proportions and rates per 100 000 population of positive test results among persons with symptoms compatible with COVID-19 born from 1979 to 1981 (aged 39-41 years) with those born from 1983 to 1985 (aged 35-37 years). A 2-sided significance threshold was set at P < .05. The study was deemed exempt by the Shamir Medical Center institutional review board as all data were deidentified. Statistical analyses were performed using R software, version 3.5.3 (R Foundation).

    Results

    Of 72 060 test results reviewed, 3064 were from patients born between 1979 and 1981 (1.02% of birth cohort of that period; 49.2% male; mean age, 40 years) and 2869 were among likely unvaccinated people born between 1983 and 1985 (0.96% of total birth cohort; 50.8% male; mean age, 35 years). There was no statistically significant difference in the proportion of positive test results in the BCG-vaccinated group (361 [11.7%]) vs the unvaccinated group (299 [10.4%]; difference, 1.3%; 95% CI, −0.3% to 2.9%; P = .09) or in positivity rates per 100 000 (121 in vaccinated group vs 100 in unvaccinated group; difference, 21 per 100 000; 95% CI, −10 to 50 per 100 000; P = .15). There was 1 case of severe disease (mechanical ventilation or intensive care unit admission) in each group, and no deaths were reported (Table).

    Discussion

    In this cohort of Israeli adults aged 35 to 41 years, BCG vaccination in childhood was associated with a similar rate of positive test results for SARS-CoV-2 compared with no vaccination. Because of the small number of severe cases, no conclusion about the association between BCG status and severity of disease can be reached. Although the BCG vaccine is given to protect against tuberculosis, it has also been found to exert nonspecific beneficial effects such as protection against other infectious diseases3 and to enhance immunogenicity of certain vaccines, such as the influenza vaccine.4 These effects are thought to be mediated partly by heterologous effects on adaptive immunity such as T cell–mediated cross-reactivity but also by the potentiation of innate immune response.5

    The strengths of this study are the large population-based cohort and the comparison of 2 similar age groups, thus limiting confounders to a minimum. The main limitation is the inclusion of populations who were not born in Israel, with unknown vaccination status. However, immigrants from countries that vaccinate with BCG, within these age groups, are a minority (4.9% and 4.6% of the older and younger population groups, respectively) and should not be overrepresented in one group.6 In addition, the rates per 100 000 do not represent the positivity rate in the population, as persons tested were preselected based on reported symptoms.

    In conclusion, this study does not support the idea that BCG vaccination in childhood has a protective effect against COVID-19 in adulthood.

    Section Editor: Jody W. Zylke, MD, Deputy Editor.
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    Article Information

    Corresponding Author: Ilan Youngster, MD, MMSc, Pediatric Infectious Diseases Unit, Center for Microbiome Research, Shamir Medical Center, Zerifin 70300, Israel (youngsteri@shamir.gov.il).

    Accepted for Publication: April 30, 2020.

    Published Online: May 13, 2020. doi:10.1001/jama.2020.8189

    Author Contributions: Dr Youngster had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Hamiel, Youngster.

    Acquisition, analysis, or interpretation of data: Kozer, Youngster.

    Drafting of the manuscript: Hamiel, Youngster.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Youngster.

    Supervision: Youngster.

    Conflict of Interest Disclosures: None reported.

    References
    1.
    Miller  A, Reandelar  MJ, Fasciglione  K,  et al. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. medRxiv. Preprint posted March 28, 2020. doi:10.1101/2020.03.24.20042937
    2.
    Berg  MK, Yu  Q, Salvador  CE,  et al. Mandated bacillus Calmette-Guérin (BCG) vaccination predicts flattened curves for the spread of COVID-19. medRxiv. Preprint posted May 4, 2020. doi:10.1101/2020.04.05.20054163
    3.
    Hollm-Delgado  MG, Stuart  EA, Black  RE.  Acute lower respiratory infection among bacille Calmette-Guérin (BCG)-vaccinated children.   Pediatrics. 2014;133(1):e73-e81. doi:10.1542/peds.2013-2218PubMedGoogle ScholarCrossref
    4.
    Leentjens  J, Kox  M, Stokman  R,  et al.  BCG vaccination enhances the immunogenicity of subsequent influenza vaccination in healthy volunteers: a randomized, placebo-controlled pilot study.   J Infect Dis. 2015;212(12):1930-1938. doi:10.1093/infdis/jiv332PubMedGoogle ScholarCrossref
    5.
    Netea  MG, van Crevel  R.  BCG-induced protection: effects on innate immune memory.   Semin Immunol. 2014;26(6):512-517. doi:10.1016/j.smim.2014.09.006PubMedGoogle ScholarCrossref
    6.
    Israel Central Bureau of Statistics. Jews by continent of origin, sex and age. Accessed April 25, 2020. https://www.cbs.gov.il/en/publications/Pages/2018/Immigration-Statistical-Abstract-of-%20Israel-2018-No-69.aspx
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