Revamping the BCG revaccination strategy: Records to recall, or just call it phoenix?

There may be one viewpoint on which vaccinologists agree: the protective efficacy afforded by the century-old bacillus Calmette-Guérin (BCG) vaccine against tuberculosis (TB) varies substantially, from 0 to 80%. Based on observations that a second dose of BCG vaccine during childhood, referred to as BCG revaccination, did not increase its protective efficacy in school-age Brazilian children,^1,2 BCG revaccination was abandoned in several countries, except for Russia, Portugal, Chile and Hungary [reviewed by ^3,4]. Discontinuing BCG revaccination is also endorsed by the World Health Organization (WHO).⁵ Nevertheless, and spurred in the high numbers of TB cases and associated deaths, different vaccination schedules that include BCG revaccination are being reevaluated lately using carefully designed clinical trials (CLT).

Like the famous, red-gold feathered, Greek-mythological immortal bird phoenix that cyclically regenerates, vaccination and revaccination with BCG reemerges again to be considered based on recent findings of a significant protective effect of BCG revaccination against TB⁶ and supporting its beneficial nonspecific, agnostic or heterologous effects.⁷ The COVID-19 pandemic has stimulated investigators to scrutinize the effect of BCG vaccination or revaccination as a strategy to reduce severe COVID-19 in CLT, which has led to conflicting outcomes. ^8–13

BCG vaccination has also been reported to reduce neonatal sepsis, respiratory tract infections and all-cause infant mortality.^11,14 However, when all-cause mortality following BCG revaccination was assessed in a large CLT in Malawi, Glynn et al.¹⁵ found little evidence of any beneficial effect of BCG revaccination, since the high proportion of deaths was attributable to noninfectious causes beyond infancy. Yet, the community still waits for a convincing response about novel BCG-vaccination protocols.

Like for any vaccination, BCG revaccination recommendations are based on the risk/benefit ratio. The BCG vaccine scar is typically raised in the middle and may have rounded edges. The edges of the scar may be irregular [https://www.nhs.uk/conditions/vaccinations/bcg-tb-vaccine-side-effects/]. Since BCG scarring and size may predict mycobacteria-specific T-cell responses in Australian children, Pittet et al.¹⁶ suggest focusing BCG revaccination on scar-negative individuals, although the relation between BCG scar and protection against TB remains a matter of debate. Should we simply trust in scarring of past BCG immunization as surrogate for induced anti-TB protective immune response?

The BCG batch, the BCG strain, and inadequate BCG vaccine administration are all recognized as potential factors behind the failure to develop a BCG scarring.^12,17 To consider BCG revaccination, we must acknowledge that the rate of adverse events (AE) also varies globally. While BCG vaccine batch variability was found by Soh and colleagues (2014) to affect the occurrence of AEs,¹⁸ Villanueva et al.¹⁹ did not find any association between the BCG vaccine batch and AEs. There is thus a paucity of evidence comparing the effectiveness and safety of different BCG batches.

For decades, BCG immunization given to immunocompetent children has been deemed safe.¹³ A systematic review and meta-analysis of 14 CLT elegantly dissected AEs following prime BCG vaccination, showing significant discrepancies in lymphadenitis rates in Saudi Arabia and Haiti between 1994 and 2012, and BCGosis rates in South Africa and France.²⁰ Thus, another consensus has been reached, as these records vary substantially. And what about BCG revaccination? Bannister et al.³ suggested that future CLT employing the BCG vaccine should report occurrences of AE, since they observed a small increase in the rate of mild local and systemic reactions in a systematic review. As no serious AEs were reported in immunocompetent individuals in that study, they concluded that BCG revaccination carries minimal risk.³ This finding is recalled in this issue (see below). Villanueva et al.¹⁹ reported an increased risk of injection site abscess and lymphadenopathy following BCG revaccination in Australian health care workers (HCW) during the influenza vaccination campaign.

With this in mind, a collection of original articles published in the Human Vaccines & Immunotherapeutics Journal was conceptualized to present (i) new findings in order to keep readers up to date regarding BCG revaccination and (ii) to provide a forum for debate about current knowledge about BCG vaccine AEs. Hence, the four outstanding articles published on that topic were mainly focused on the clinical and experimental data that examined protection afforded by BCG revaccination and to the potential of the vaccines to induce AEs.

Sánchez-García and colleagues²¹ assessed the safety of revaccination using the Tokyo strain in BCG-primed HCW in the context of COVID-19. As expected, both early and late local AEs were common, and local symptoms seemed to be decreased from 24–36 hours to 7 days of follow-up. Severe AEs were very few and limited to subcutaneous abscesses and lymphadenitis. This is in striking contrast to the earlier findings by Villanueva et al.¹⁹ In the current issue, Sánchez-García and colleagues²¹ concluded that BCG revaccination in a previously immunized Mexican population was safe.

In the BRACE study, Villanueva and colleagues²² prospectively evaluated the impact of BCG revaccination with the Danish strain on local AEs in HCW from three continents. Information on the strain participants has received for their primary BCG vaccination was not available. In this study, BCG revaccination was again associated with an increased frequency of mild injection site reactions, as well as earlier onset and shorter duration of self-limiting erythema and swelling, when compared to BCG-naïve individuals.

Lately, vaccine hesitancy has been progressively reported in Brazil, closely linked to socioeconomic factors.²⁵ Yamoah and colleagues²³ stated the importance of minimizing AEs following immunization to increase confidence and reduce vaccine hesitancy in BCG vaccination campaigns. They surveyed, in a cross-sectional CLT, the adherence of HCWs to pre-vaccination precautions and AEs during BCG vaccination in Ghana. Again, BCG revaccination was linked to the occurrence of abscess, injection site pain and redness, among others. However, overall, adherence to pre-BCG vaccination precautions and AEs reporting were satisfactory.

Finally, a recent audit conducted by Savul & Duthie²⁴ revealed that the BCG vaccination rate for newborns in a Scottish region was roughly 90% for three consecutive years. This is an improvement from previous periods. The authors highlighted the need to enhance the electronic system and increase awareness about the BCG vaccine to further boost its coverage in that setting.

It is imperative to leverage a biological standardization program to develop and revise specific recommendations for both BCG vaccine production and quality control worldwide. In 2011, the WHO Expert Committee on Biological Standardization met to set out revised WHO Recommendations in relation to those concerns.²⁶ It is expected that harmonized guidelines and recommendations for manufacturers and regulatory authorities will be proposed by the WHO. This activity is critical to ensure the quality of essential vaccines in a global market. And, as recently reported, the BCG vaccine manufacturers very likely follow similar procedures, yet differences in production or preservation practices might still remain, leading to changes in viability and capacity to induce protective immune responses.²⁷ Therefore, these four articles published in 2023, together with those reported earlier, reinforce the importance of additional CLT to dissect the immune profiles leading to protection against TB, and immunization schedules related to BCG vaccine AEs, in order to identify the best safety protocol. There is still a long road ahead to follow up on the right direction toward a safer BCG revaccination strategy, including follow-up to properly stress efficacy against TB and other infectious diseases. The clock is ticking for the resurrection of BCG revaccination policy.

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The author(s) reported that there is no funding associated with the work featured in this article.