https://orcid.org/0000-0002-6297-7429
ABSTRACT
The bacille Calmette-Guérin (BCG) vaccine is administered in many countries as part of their vaccination schedules. Epidemiologic studies have suggested a possible benefit of this vaccine in the context of the COVID-19 pandemic and other respiratory infections. We aimed to assess the safety of this intervention in BCG-primed adults. Adult health care workers (n = 451) received a single intradermal application of the BCG vaccine (Tokyo 172 strain) in the deltoid region of the right arm. Follow-up (30 days) calls and clinical inspections were guided using a standardized data sheet to assess local and systemic reactions. Early local reactions were common at 24 h and 7 days, such as erythema (74.9%, 69.2%), induration (55.7%, 59%), a papule (53.4%, 47.7%), and edema (48.3%, 38.1). Local symptoms (pruritus 44.8%, heat 16.2%, and pain 34.8%) were less frequent at day 7. Late expected reactions (14 and 30 days) included the formation of crusts (39.6% and 63.9%), a pustule (36.6% and 17%), or ulcers (28.8% and 17.7%). Severe reactions were limited to subcutaneous abscesses (2%) and lymphadenitis (<1%).
Previous data have shown that through nonspecific innate immunity training, vaccination can reduce morbidity and mortality from other diseases better than those that the vaccine is intended to protect.Citation1,Citation2 The bacille Calmette-Guérin (BCG) vaccine is currently administered in many countries, including Mexico, to prevent tuberculosis (TB) meningitis and disseminated TB in infants.Citation3 Preceding studies suggest that BCG may offer a decrease in acute respiratory tract infections,Citation4 sepsis, and a positive effect in bladder cancer in adults.Citation5
Initial unavailability of a specific COVID-19 vaccine or treatment motivated strategies to reduce the morbidity and mortality of COVID-19, leading to retrospective and observational studies whose findings suggested a protective effect of BCG vaccination for SARS-CoV-2 infection.Citation6,Citation7 In contrast, a systematic review and meta-analysis of experimental studies determined no protective effect of BCG immunization against COVID-19; however, other beneficial effects, such as better protection against tuberculosis and non-tuberculosis respiratory infections were found.Citation8 Although epidemiological reports have demonstrated that this intervention is safe among adults, experimental data is limited and inconsistent.Citation9,Citation10 Earlier studies were conducted on small sample sizes and particular demographics or clinical populations using different M. bovis strains.Citation11–13 Therefore, we assessed the safety of BCG immunization in BCG-primed adults. We summarize the local and systemic reactions related to BCG revaccination.
We conducted our study among health care workers in the “Dr. José E. González” University Hospital. The research protocol was approved and registered by the institutional review boarding committee and Clinical Trials (NCT04461379). Written informed consent was obtained before enrollment. Key exclusion criteria were: pediatric population, immunocompromised patients, allergy to vaccine components, fever, any other previous vaccination within four weeks before enrollment, tuberculosis, cancer, pregnancy, COVID-19, positive anti-SARS-CoV-2 test, use of anti-tuberculosis or immunosuppression drugs, hydroxychloroquine, chloroquine, azithromycin, lopinavir/ritonavir, ivermectin, or any drug used to treat COVID-19. We excluded subjects with active previous COVID-19 infection, a positive anti-SARS-CoV-2 test, or using any drug to treat COVID-19 to avoid confounding in the protective BCG effect and on reactions and adverse events. Participants received a single intradermally application of the BCG vaccine (0.1 mL, Tokyo 172 strain) in the deltoid region of the right arm. A medical history was obtained and BCG vaccination during childhood was confirmed by the scar inspection. We performed a telephone follow-up call (<36 hours, 7 days, 14 days, and 30 days) and clinical inspections to assess local normal and systemic expected reactions. In order to reduce the risk of recall bias, the frequency of follow-up was high. We performed demographic comparisons at baseline as recommended.Citation14 Categorical variables were summarized in frequencies and percentages; numerical variables in means and standard deviations or medians and interquartile ranges (IQR). Pearson’s Chi-square tests were performed for hypothesis testing in categorical variables and Student’s t-test in numerical variables. A p-value of < .05 was considered statistically significant. All the analyses were performed in SPSS V25.0 (IBM, NY, USA).
BCG vaccine was administered to 451 participants (61.8% females, age 36.9 ± 13.1 years). The most common local reaction was erythema, which was present in 338 (74.9%) participants at the initial 24–36 hours and decreased to 312 (69.2%) at seven days. Other frequent local events were induration, papule formation, pruritus, edema, and local pain (). The formation of a pustule increased from 30 (6.7%) at 24–36 hours to 126 (27.9%) at seven days. The formation of a pustule was maintained for several weeks. Also, the formation of an ulcer increased from 5 (1.1%) at 24–36 hours to 25 (7.8%) at seven days. The most common systemic reactions was a headache, which occurred in 91 (20.2%) at 24–36 hours and decreased to 44 (9.8%) at seven days. Other systemic reactions were malaise and myalgias, which were present respectively in 41 (9.1%) and 34 (7.5%) patients initially but decreased to 16 (4.2%) and 8 (1.8%) at seven days ().
Table 1. Local and systemic reactions following BCG vaccination.
The most frequent late local site reaction was the formation of a crust. This was present in 178 subjects (39.6%) at 14 days and increased to 288 (63.9%) at 30 days, followed by the formation of a pustule, which was present in 165 (36.7%) participants at 14 days but decreased to 75 (17%) at day 30. Ulcer formation decreased from 130 (28.8%) at 14 days to 80 (17.7%) at 30 days. Among the most serious reactions were the formation of a subcutaneous abscess and a keloid scar which were present in 10 (2.2%) and 6 (1.3%) at day 14, respectively. The formation of a subcutaneous abscess resolved in half of the patients on day 30. In contrast, the presence of a keloid scar increased to 22 (5%) at day 30. Ulcer formation at 14 days was greater in men (36% vs. 24.5%, p = .009). The development of lymphadenitis (simple lymphadenopathy >1 cm in size and non suppurative) was present in 2 (0.4%) at day 14, and both events were still present on day 30. Finally, only 1 (0.2%) patient developed a mild rash reaction in the ipsilateral arm and thorax ().
Early local reactions such as erythema, induration, a papule, and edema, were frequent in 74.9%, 55.7%, 53.4%, and 48.3% of the participants at 24 h, respectively. Local symptoms such as pruritus, heat, pain, and systemic reactions were also less frequent. Among the latter, headaches were reported in less than a quarter, followed by malaise in one-tenth of the population. Late reactions (14 days) included the formation of crusts, a pustule, or ulcers in 39.6%, 36.7%, and 28.8% of the participants, respectively. Severe reactions were limited to local reactions.
BCG revaccination and the associated adverse effects were first observed in children, estimating one adverse event per 2,580 revaccinations in Brazilian schoolchildren.Citation11 Cunha et al. reported 13 cases of children and adolescents with complications, such as abscesses requiring antibiotics and additional anti-tuberculosis drugs due to BCG revaccination occurring between 21 days and nine months after revaccination.Citation15 Mild-to-moderate injection-site reactions were common in adolescents revaccinated with BCG, with > 98% having at least one event.Citation12 Fjallbrant et al. observed no side-effects associated with BCG revaccination in 16 young adults using the Danish strain 1331.Citation16 In contrast, a five-year retrospective study revealed complications after revaccination with BCG, such as subcutaneous ulcers and deep chronic ulcers.Citation17 Erythema, induration, ulceration, and residual scar were reported by Hatherill et al.Citation13 in 82 BCG (Danish strain 1331) revaccinated adults with latent M. tuberculosis infection. No regional lymphadenitis or morbidity was recorded. In a recent trial, Villanueva et al. found that BCG revaccination was associated with a higher risk of developing a local adverse reactions compared with initial BCG vaccination in healthcare workers (median age, 41 years). Similar to our observations, they observed erythema in 87% of the participants, and lymphadenopathy in 3% of the subjects.Citation18 Rho et al. determined that the incidence of adverse events per 100,000 BCG doses was found to be 41.6 for intradermal Danish strains and 25.9 for 100,000 intradermal Tokyo strains.Citation19 These previous observations may support our findings. More recently, adverse effects of BCG revaccinations were investigated in leprosy patients and their contacts (n = 72), mainly consisting of skin ulcers.Citation20 Local reaction events were common, while systemic reactions were not. The above-mentioned studies show that BCG revaccination is safe and well-tolerated with similar adverse effects to those experienced in the primary BCG vaccination. In general, our findings related to the adverse effects associated with BCG revaccinations were in accordance with previous studies.
Several epidemiological studies have suggested a possible benefit from BCG immunization for preventing severe COVID-19. Our results provide confidence for the execution of experimental trials to assess BCG vaccine efficacy to prevent or attenuate COVID-19. There were 27 registered ongoing trials evaluating its effectiveness and safety in several countries. If these trials provide positive results, BCG vaccination can be considered an immune reinforcement, along with the administration of COVID-19-specific vaccination.
This study is strengthened by its large sample size, the inclusion of adult population, an absolute retention rate of the participants, and a periodical follow-up period. However, these mentioned characteristics should be balanced with the quasi-experimental study design and the non specific immunity provided by the BCG vaccine in comparison with the specific COVID-19 vaccines. Currently, there are 46 approved COVID-19 vaccines developed using different platforms, such as the updated Pfizer/BioNTech (Comirnaty bivalent original/Omicron BA.4/BA.5) and Moderna (Spikevax bivalent original/Omicron BA.4/BA.5) vaccines.Citation21 In conclusion, our results suggest that BCG vaccine administration in a previously immunized adult population is safe. Early mild local reactions and symptoms were common and severe reactions were limited to local injection site signs.
Acknowledgments
Financial support was provided by the Endocrinology Division, Department of Internal Medicine, “Dr. José E. González” University Hospital. We thank Sergio Lozano-Rodríguez, M.D., for his critical reading and language editing of the manuscript.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Additional information
Funding
References
- Rousseau MC, Parent ME, St-Pierre Y. Potential health effects from non-specific stimulation of the immune function in early age: the example of BCG vaccination. Pediatr Allergy Immunol. 2008;19(5):438–4. doi:10.1111/j.1399-3038.2007.00669.x.
- Blok BA, Arts RJ, van Crevel R, Benn CS, Netea MG. Trained innate immunity as underlying mechanism for the long-term, nonspecific effects of vaccines. J Leukoc Biol. 2015;98(3):347–56. doi:10.1189/jlb.5RI0315-096R.
- Luca S, Mihaescu T. History of BCG vaccine. Maedica (Bucur). 2013;8:53–8.
- Wardhana DE, Sultana A, Mandang VV, Jim E. The efficacy of Bacillus Calmette-Guerin vaccinations for the prevention of acute upper respiratory tract infection in the elderly. Acta Med Indones. 2011;43:185–90.
- Sylvester RJ, van der MA, Lamm DL. Intravesical Bacillus Calmette-Guerin reduces the risk of progression in patients with superficial bladder cancer: a meta-analysis of the published results of randomized clinical trials. J Urol. 2002;168(5):1964–70. doi:10.1016/S0022-5347(05)64273-5.
- Miller A, Reandelar MJ, Fasciglione K, Roumenova V, Li Y, Otazu GH. Correlation between universal BCG vaccination policy and reduced morbidity and mortality for COVID-19: an epidemiological study. MedRxiv. 2020;2020:2020.03. 24.20042937.
- Joy M, Malavika B, Asirvatham ES, Sudarsanam TD, Jeyaseelan L. Is BCG associated with reduced incidence of COVID-19? A meta-regression of global data from 160 countries. Clin Epidemiol Global Health. 2021;9:202–3. doi:10.1016/j.cegh.2020.08.015.
- Trunk G, Davidović M, Bohlius J. Non-specific effects of Bacillus Calmette-Guérin: a systematic review and meta-analysis of randomized controlled trials. Vaccines (Basel). 2023;11(1):121. doi:10.3390/vaccines11010121.
- Curtis N, Sparrow A, Ghebreyesus TA, Netea MG. Considering BCG vaccination to reduce the impact of COVID-19. Lancet. 2020;395(10236):1545–6. doi:10.1016/S0140-6736(20)31025-4.
- Wen J, Liu Q, Tang D, He JQ. Efficacy of BCG vaccination against COVID-19: systematic review and meta-analysis of randomized controlled trials. J Clin Med. 2023;12(3):1154. doi:10.3390/jcm12031154.
- Dourado I, Rios MH, Pereira SM, Cunha SS, Ichihara MY, Goes JC, Rodrigues LC, Bierrenbach AL, Barreto ML. Rates of adverse reactions to first and second doses of BCG vaccination: results of a large community trial in Brazilian schoolchildren. Int J Tuberc Lung Dis. 2003;7:399–402.
- Nemes E, Geldenhuys H, Rozot V, Rutkowski KT, Ratangee F, Bilek N, Mabwe S, Makhethe L, Erasmus M, Toefy A, et al. Prevention of M. tuberculosis infection with H4: IC31 vaccine or BCG revaccination. N Engl J Med. 2018;379(2):138–49. doi:10.1056/NEJMoa1714021.
- Hatherill M, Geldenhuys H, Pienaar B, Suliman S, Chheng P, Debanne SM, Hoft DF, Boom WH, Hanekom WA, Johnson JL, et al. Safety and reactogenicity of BCG revaccination with isoniazid pretreatment in TST positive adults. Vaccine. 2014;32(31):3982–8. doi:10.1016/j.vaccine.2014.04.084.
- Knol MJ, Groenwold RHH, Grobbee DE. P-values in baseline tables of randomized controlled trials are inappropriate but still common in high impact journals. Eur J Prev Cardiol. 2012;19(2):231–2. doi:10.1177/1741826711421688.
- Cunha AJ, Sant’anna CC, Mannarino R, Labanca TC, Ferreira S, March MF. Adverse effects of BCG revaccination: a report on 13 cases from Rio de Janeiro, Brazil. Int J Tuberc Lung Dis. 2002;6:1110–13.
- Fjällbrant H, Ridell M, Larsson LO. Primary vaccination and revaccination of young adults with BCG: a study using immunological markers. Scand J Infect Dis. 2007;39(9):792–8. doi:10.1080/00365540701367777.
- El Ouazzani H, Lamsyah H, Alioua Z, Rhorfi I, Rguibi M, Ghfir M, Abid A, Sedrati O, Alaoui-Tahiri K. Complications de la revaccination par le BCG: 12 observations. Annales de Dermatologie et de Vénéréologie. 2007;134(2):129–32. doi:10.1016/S0151-9638(07)91603-8.
- Villanueva P, Wadia U, Crawford N, Messina NL, Kollmann TR, Lucas M, Manning L, Richmond P, Pittet LF, Curtis N, et al. Revaccination with Bacille Calmette-Guérin (BCG) is associated with an increased risk of abscess and lymphadenopathy. NPJ Vaccines. 2022;7(1):6. doi:10.1038/s41541-021-00421-5.
- Roh EJ, Lee YK, Lee MH, Kim M-K, Kim TE, Lee SG, Chung EH. Investigation of adverse events following bacille Calmette-Guérin immunization using immunization safety surveillance system in Korea centers for disease control and prevention. Clin Exp Vaccine Res. 2020;9(2):133–45. doi:10.7774/cevr.2020.9.2.133.
- Richardus R, van Hooij A, van den Eeden SJ, Wilson L, Alam K, Richardus JH, Geluk A. BCG and adverse events in the context of leprosy. Front Immunol. 2018;9:629. doi:10.3389/fimmu.2018.00629.
- Yadav T, Kumar S, Mishra G, Saxena SK. Tracking the COVID-19 vaccines: the global landscape. Hum Vaccin Immunother. 2023;19(1):2191577. doi:10.1080/21645515.2023.2191577.