Intravenous BCG Immunization Prevents Tuberculosis in Macaques

By Will Boggs MD

January 13, 2020

NEW YORK (Reuters Health) - Intravenous BCG immunization prevents or substantially limits tuberculosis in rhesus macaques, researchers report.

"The ability to fully prevent detectable TB infection in the majority of animals in a highly susceptible model for approximately 6 months by administering BCG by the IV route was an extraordinary finding which paves the way for understanding how to dramatically limit TB infection by a vaccine," Dr. Robert A. Seder of the National Institute of Allergy and Infectious Diseases, in Bethesda, Maryland, told Reuters Health by email.

BCG vaccine (live, attenuated Mycobacterium bovis), administered intradermally at birth, provides protection against disseminated TB in infants, but it has variable efficacy against pulmonary disease in adolescents and adults.

Studies performed decades ago suggested that administration of BCG by aerosol or IV routes enhanced protection in nonhuman primates challenged shortly after immunization.

Dr. Seder and colleagues investigated whether high doses of IV BCG could elicit a high frequency of systemic and tissue resident T cells and thereby provide durable protection against Mycobacterium tuberculosis infection in highly susceptible rhesus macaques.

They vaccinated these macaques with 50 million colony-forming units (CFUs) by intradermal (IDhigh), aerosol (AE), or IV routes; with 50 million CFUs by aerosol and 500K CFU intradermally (AE/ID); or with the standard human dose (500K CFUs) intradermally (IDlow).

Only IV BCG vaccination resulted in significant and sustained recruitment of T cells to the airways and substantially altered the ratio of T cells to macrophages, the researchers report in Nature.

Similarly, compared with intradermal or aerosol delivery, IV immunization induced substantially more antigen-responsive CD4 and CD8 T cell responses in blood, spleen, bronchoalveolar lavage, and lung lymph nodes and induced a high frequency of antigen-responsive T cells across all lung parenchymal tissues.

When challenged six months after BCG immunization with a highly pathogenic strain of tuberculosis, four macaques in the IDhigh and AE/ID groups showed evidence of partial protection, whereas nine of 10 macaques in the IV group showed no evidence of infection at 12 weeks.

By four weeks and throughout infection, granulomas were detected in all unvaccinated macaques and in the IDlow, IDhigh, AE, and AE/ID groups, whereas six of 10 macaques in the IV group had no granulomas throughout infection.

Mycobacterial burden at necropsy, the primary measure of protection, was only slightly lower in the IDlow group than in the unvaccinated group. Meanwhile, the median total thoracic mycobacterial burden was more than 100,000-fold lower in the IV-BCG-immunized group than in the IDlow group, and six of these 10 IV-BCG-immunized macaques had no detectable mycobacteria in any tissue measured.

Mycobacterial burdens in the IDhigh, AE, and AE/ID groups were similar to those in the IDlow group.

Unlike all the other groups, the IV BCG group had low to undetectable primary or anamnestic T cell and antibody responses after TB infection, which suggests rapid elimination of mycobacteria after challenge, the authors say.

In multiple regression analyses, the route of BCG vaccination was the primary determinant of mycobacterial control, with IV being the only regimen that provided significant protection.

"The findings that IV immunization leads to a much higher frequency of tissue resident T cells in the lung than the standard ID route of immunization shows how simply changing the route of immunization can have a dramatic effect on generating responses at tissue sites which likely are critical for mediating protection," Dr. Seder said.

"BCG will continue to be given at birth by the ID route around the world since it provides protection against system manifestations of infection through infancy," he said. "Our findings suggest that giving BCG by the IV route to young adolescents and adults who are at greatest risk of pulmonary TB could be highly effective at preventing infection and/or disease."

Dr. Helen McShane of The Jenner Institute at the University of Oxford, in the UK, who has researched various aspects of tuberculosis, told Reuters Health by email, "The paper is very interesting. It confirms 2 previously published studies (Barclay et al and Sharpe et al) published in about 1970 and 2016, respectively, which showed that IV BCG was much more protective than ID BCG."

"It provides a very useful model for us to identify immune correlates of protection and to understand more about TB vaccine-induced immunity," she said. "This will help us in developing an effective new TB vaccine."

"But, I do not think IV BCG is a deployable vaccine," added Dr. McShane, who was not involved in the study. "WHO recommendations are that BCG is administered as close to birth as possible. This would not be feasible with IV administration. And although in the paper the authors suggest that using IV BCG as a booster vaccine in adolescence might be feasible, this is not the strategy that was tested here."

SOURCE: Nature, online January 2, 2020.