Randomized clinical trial of BCG vaccine in patients with convalescent COVID-19: Clinical evolution, adverse events, and humoral immune response

Mehrsa Jalalizadeh, Keini Buosi, Franciele A V Dionato, Luciana S B Dal Col, Cristiane F Giacomelli, Karen L Ferrari, Ana Carolina Pagliarone, Patrícia A F Leme, Cristiane L Maia, Reza Yadollahvandmiandoab, Quoc-Dien Trinh, Kleber G Franchini, Marcio C Bajgelman, Leonardo O Reis, Mehrsa Jalalizadeh, Keini Buosi, Franciele A V Dionato, Luciana S B Dal Col, Cristiane F Giacomelli, Karen L Ferrari, Ana Carolina Pagliarone, Patrícia A F Leme, Cristiane L Maia, Reza Yadollahvandmiandoab, Quoc-Dien Trinh, Kleber G Franchini, Marcio C Bajgelman, Leonardo O Reis

Abstract

Background: The Bacillus Calmette-Guérin (BCG) vaccine may confer cross-protection against viral diseases in adults. This study evaluated BCG vaccine cross-protection in adults with convalescent coronavirus disease 2019 (COVID-19).

Method: This was a multicenter, prospective, randomized, placebo-controlled, double-blind phase III study (ClinicalTrials.gov: NCT04369794).

Setting: University Community Health Center and Municipal Outpatient Center in South America.

Patients: a total of 378 adult patients with convalescent COVID-19 were included.

Intervention: single intradermal BCG vaccine (n = 183) and placebo (n = 195).

Measurements: the primary outcome was clinical evolution. Other outcomes included adverse events and humoral immune responses for up to 6 months.

Results: A significantly higher proportion of BCG patients with anosmia and ageusia recovered at the 6-week follow-up visit than placebo (anosmia: 83.1% vs. 68.7% healed, p = 0.043, number needed to treat [NNT] = 6.9; ageusia: 81.2% vs. 63.4% healed, p = 0.032, NNT = 5.6). BCG also prevented the appearance of ageusia in the following weeks: seven in 113 (6.2%) BCG recipients versus 19 in 126 (15.1%) placebos, p = 0.036, NNT = 11.2. BCG did not induce any severe or systemic adverse effects. The most common and expected adverse effects were local vaccine lesions, erythema (n = 152; 86.4%), and papules (n = 111; 63.1%). Anti-severe acute respiratory syndrome coronavirus 2 humoral response measured by N protein immunoglobulin G titer and seroneutralization by interacting with the angiotensin-converting enzyme 2 receptor suggest that the serum of BCG-injected patients may neutralize the virus at lower specificity; however, the results were not statistically significant.

Conclusion: BCG vaccine is safe and offers cross-protection against COVID-19 with potential humoral response modulation.

Limitations: No severely ill patients were included.

Keywords: BCG; COVID-19; IgG; SARS-CoV-2; convalescence; immunomodulation; neutralization; safety.

Conflict of interest statement

The authors declare no competing interests.

© 2022 The Association for the Publication of the Journal of Internal Medicine.

Figures

Fig. 1
Fig. 1
Flowchart of study inclusion, exclusion, and analysis.
Fig. 2
Fig. 2
Symptomatic analysis of patients. Each symptom is given a number, and the count of symptoms for each patient for each visit is calculated to understand the difference in speed of recovery. For example, if the patient had headache and fatigue on visit T1, the symptom count on T1 would be 2. The graphs show no significant difference between Bacillus Calmette–Guérin (BCG) and placebo on recovery speed except for visit T2 when BCG recipients are slightly less symptomatic.
Fig. 3
Fig. 3
Serology analysis of patients. (a) and (b) show anti–severe acute respiratory syndrome coronavirus 2 N protein immunoglobulin G (IgG) titer on each visit. There was no significant difference on this titer between Bacillus Calmette–Guérin (BCG) and placebo. (c) and (d) show percent neutralization of recombinant ACE2 receptor assay of patient sera. (e) and (f) are neutralization divided by IgG titer, showing a slightly lower result at T4 in BCG recipients.

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Source: PubMed

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