BCG Vaccines Best Repositioned for Prophylaxis than Therapeutic Investigation

BCG vaccines best repositioned for prophylaxis than therapeutic investigation yet may only offer reduced disease severity, not full protection, investigators say

• Nonspecific impact on the immune system during infection could be risky
• BCG vaccines only a stopgap; wide use threatens availability in TB territories
• Trial comparison moot as trials are designed specifically per country

The Bacillus Calmette-Guérin (BCG) vaccines being investigated for COVID-19 are likely to have a better shot in the prophylactic setting than in patients positive for SARS-CoV-2, investigators said. These vaccines are more inclined to reduce the risk of severe disease rather than offering complete protection due to their nonspecific mechanism, they noted.

An investigator in the Brazil-based, Phase IV therapeutic trial (NCT04369794) noted the potential of BCG vaccines to boost lymphocytes to attack SARS-CoV-2, coupled with its positive side-effect profile, makes it worthy for investigation in the treatment setting. However, investigators in prophylactic trials were more skeptical since patients’ immune systems are more dynamic during an active infection and there is a heightened risk of triggering a cytokine storm.

However, BCG vaccines should not be considered for wide preventive use, interviewed investigators agreed. The vaccines should be limited to healthcare workers and the elderly, as extensive use would negatively impact countries with endemic tuberculosis (TB), which the vaccine is designed for, they added. The vaccine’s efficacy ceiling is 50% protection, and so is only intended as a temporary solution until a more targeted vaccine is available, they explained.

BCG vaccines are being studied in eight preventive trials recruiting healthcare workers—Australia (NCT04327206), Colombia (NCT04362124), Denmark (NCT04373291), Egypt (NCT04350931), Mexico (NCT04461379), the Netherlands (NCT04328441), South Africa (NCT04379336), and the US (NCT04348370)—according to ClinicalTrials.gov. Two additional preventive trials in India (NCT04475302) and the Netherlands (NCT04417335) are specifically enrolling people who are more than 60 years old, while a Greece-based trial (NCT04414267) is recruiting people who are more than 50 years old.

Because these trials are specifically designed for each county, are powered differently, and utilize different strains, investigators noted comparisons of the forthcoming results would not be ideal. Only the two trials in the Netherlands have completed recruitment, with the Phase III healthcare worker trial having a primary completion date of March 2021.

Therapeutic potential draws skepticism

The rationale behind using BCG vaccines as a COVID-19 therapy comes from their use in early-stage bladder cancer, explained therapeutic setting investigator Dr. Leonardo Reis, professor of urology, University of Campinas, S?o Paulo. The vaccine boosts the immune system to produce a significant number of lymphocytes to attack antigens, he explained.

Further supporting its therapeutic exploration is its positive safety profile, Reis noted. While there is research showing the live attenuated BCG vaccine could reactivate in immunocompromised people like those with human immunodeficiency virus (HIV), this research is from the 1980s and maybe outdated, noted in South Africa trial investigator Dr. Caryn Upton, scientific officer, TASK Research Center, Cape Town.

However, preventive setting investigators were unconvinced of the vaccine’s therapeutic potential. Once a person contracts SARS-CoV-2, the immune system becomes more dynamic, making it harder to pinpoint when the vaccine should be administered, noted US trial investigator Dr. Andrew DiNardo, assistant professor, infectious diseases, Baylor College of Medicine. However, Reis noted the Brazil-based trial, which is the only BCG vaccine study in this setting, is recruiting patients within a narrow window. The 1,000-patient trial excludes those who have symptoms for more than 14 days, recruiting those with laboratory-confirmed diagnosis or people who were in close contact with a COVID-19 patient and is showing symptoms.

In the therapeutic setting, it could be too late for the patient by the time the vaccine takes effect, added US trial investigator Dr. Moshe Arditi, director, Infectious and Immunological Research Center, Cedars-Sinai Medical Center, California. However, the couple of weeks it may take the vaccine to reach peak efficacy may be enough to boost a response against the infection, Reis noted. In the therapeutic setting, the dose required for efficacy in each patient may vary, DiNardo added. The therapeutic trial is using 0.1ml of vaccine, which contains 1–8x 1 million colony-forming units.

However, BCG vaccines’ nonspecific impact on the immune system for COVID-19 could mean there may be a negative ripple effect to vaccinating infected patients whose immune systems are already upregulated, noted Netherlands trial investigator Dr. Thijs ten Doesschate, internal medicine resident, University Medical Center Utrecht. The vaccine could speed up the cytokine storm syndrome, explained Upton.

BCG vaccines only a placeholder

While there is higher enthusiasm for BCG vaccines in the preventive setting, investigators nonetheless emphasized it should only be used in specific populations. There may not be enough doses for widespread use, and doses could be diverted from territories using them for protection from TB, which the vaccine is designed for, Arditi noted. Even if its use is expanded to the general population, it should be restricted to countries where the vaccine is in the national vaccination schedule, as there would already be established distribution infrastructures, Doesschate added.

Upregulation of production could be challenging since it is a live attenuated vaccine, Doesschate said. Even before the COVID-19 pandemic, there have been BCG vaccine shortages, Upton added.

Wide uptake may cause vaccine receivers to think they are highly protected when they are not, noted an investigator in a retrospective trial investigating BCG vaccine boosters in the United Arab Emirates (UAE) healthcare workers. BCG vaccines are only expected to offer 50% protection at most, as they are not specific to COVID-19, DiNardo and Doesschate said.

Healthcare workers are the target for most prophylactic trials because they are at a threefold increased risk of contracting SARS-CoV-2, DiNardo explained. The Phase III India trial and Phase IV Netherlands study specifically recruit the elderly, which is the population with the highest disease burden, Arditi added. Elderly people are less sensitive to vaccines with specific targets, and so a nonspecific vaccine such as the BCG vaccine could potentially be ideal, he added.

In an 11 August MedRxiv preprint, the aforementioned UAE trial showed none of the 71 healthcare workers who received a BCG vaccine booster got infected, while 19 of 209 workers who received the vaccine for the first time were positive for SARS-CoV-2. Despite being from a retrospective study, these results are still valuable as they show a booster would have a protective effect, the UAE trial investigator said. Vaccine-na?ve people may also benefit, as preclinical investigations have shown BCG vaccines’ may be active for three years after injection, Doesschate noted. 

Preventive trial differences in bar comparisons

While there are eight BCG vaccine trials in the prophylaxis setting recruiting healthcare workers, each has a different design. Five of these trials have a primary endpoint looking into COVID-19 incidence, with the Phase III Australia and Mexico trials featuring disease severity as a coprimary endpoint. The Phase III Mexico and South Africa trials have hospitalization rate primary endpoints.

Considering the BCG vaccine’s nonspecific mechanism, it may be best suited to downgrading severity risk rather than reducing infection incidence, Arditi noted. While not completely protective, BCG vaccines may be able to decrease the viral load and in turn, reduce the risk of severe disease, he explained. The US Phase IV trial has disease severity as a secondary endpoint.  

Phase III Denmark- and Netherlands-based trials are primarily investigating unplanned absenteeism. However, absenteeism reports would be influenced by factors beyond COVID-19, Upton said. The absenteeism endpoint was the most clinically important measure when the trials initiated at the pandemic’s start, Doesschate explained.  

The two preventive trials specifically recruiting people ages 60 years and older are based in India and the Netherlands. The India-based study has a mortality endpoint, whereas the Netherlands-based trial is investigating hospital admission rates. Such endpoint choices depend on what is relevant locally, as the latter would be more valuable in counties with low mortality but high hospitalization rates, Upton explained.

The various healthcare worker prophylactic trials are investigating different strains of BCG vaccines, and there may be potency differences, DiNardo said. These different strains could be a contributor to why COVID-19 rates vary among the countries with BCG vaccines in their vaccination schedules, added the UAE trial investigator.

The Danish and Tokyo strains cause a more aggressive effect on the immune system, Upton said. Of the seven healthcare worker-based preventive, which list the strains being used, five are using the Danish strain, while the Mexico study uses the Tokyo strain, and the US trial investigating the Tice strain. Nonetheless, it is unclear whether strain differences are clinically significant in COVID-19, Doesschate noted.

Comparing the various prophylactic trials is nevertheless inappropriate considering they are country-specific trials and are designed differently, DiNardo said. The various trials are also powered differently, Doesschate noted. Prophylactic trials in healthcare workers have enrollment goals ranging from 500 to 1,800 people. The Egypt trial divides patients in a 2:1 ratio with a saline comparator, while others use 1:1.

by Reynald Castaneda in London