Living vaccines revival

First administered in 1921, the BCG vaccine has slashed deaths from TB. Now, it appears BCG and other live vaccines may protect against a range of infections. Anthony King reports.

Tuberculosis claimed an estimated 1bn lives in the past two centuries and – in the absence of a pandemic – remains the top infectious disease killer globally. First to receive the BCG vaccine was an infant at a Paris hospital, whose mother had died of TB. This was a live bovine strain of bacteria – Mycobacterium bovis, a cousin to human M. tuberculosis that causes TB – that had been weakened over many years by its developers, Albert Calmette and Camille Guérin.

But along with slashing TB deaths, Calmette noted a decline in all-cause mortality, again observed by a doctor when BCG was introduced into Sweden in the 1930s.

In more recent times, evidence has amassed for live vaccines having a slew of unintentional positive health effects. At the same time, protein subunit vaccines and now mRNA vaccines have increasingly been viewed as the future of vaccines, with live vaccines viewed as ‘old hat’. Yet some vaccinologists argue that, rather than being outmoded, the medical community must reconsider live vaccines’ benefits for unrelated diseases. ‘Usually, it is assumed that you assess the overall impact of a vaccine by looking at the specific benefits, and subtracting any harm,’ says Christine Stabell Benn, Professor of global health at the University of South Denmark. ‘But we have discovered a third group of vaccine effects – the nonspecific effects.’

These effects have been most notable in infants, whose immune systems are damped down to prevent antagonism with the mother’s body. But this can leave them vulnerable to infectious diseases. Benn proposed that live vaccines better prepare the immune system of young children against infectious diseases, especially deadly conditions such as sepsis. Her husband Peter Aaby noted that when live measles vaccine (MMR) was introduced into a naive community in Guinea-Bissau, all-cause mortality fell by 70% in children (Journal of Infection, 1984, 8, 13). Aaby and Benn subsequently began studying BCG. Ordinarily, low birth weight children do not receive BCG until after six weeks. This allowed Benn and Aaby to randomly assign these children either to BCG or to the usual delayed BCG jab.

Randomised clinical trials found significant declines in mortality during the first month of life in babies vaccinated earlier. ‘This was a purely nonspecific effect because children don’t die from TB during the first month of life,’ says Benn. Getting earlier BCG especially reduced the risk of dying from septicaemia, she adds. A separate group at the London School of Hygiene & Tropical Medicine in 2022 confirmed that BCG and diphtheria-tetanus-pertussis vaccination reduced infant mortality in Ghana and Tanzania (Vaccine, 2022, 40, 3737). The Danish group also found that people who had received smallpox and BCG vaccine at school in Denmark scored a 40% lower risk of dying up to age 45 from infectious disease (J. Epidemiol., 2017, 46, 695).

Beyond BCG

BCG may not be the only live vaccine delivering unexpected upsides. Aaby believes that the live oral polio vaccine (OPV) reduced the risk of death from diseases other than polio by as much as 25% (Clin. Infect. Dis., 2021, 72, e596). This led some vaccinologists to argue against the removal of OPV – live polio vaccine can in rare instances cause a polio infection, but they say that the health benefits from the live vaccine far outweigh any costs (Lancet, 2016, 387, 1054). ‘This is not just a BCG story,’ says Ofer Levy, a vaccinologist at Harvard Medical School in Boston, US. ‘People are now also looking at off-target benefits from measles, mumps and rubella (MMR), for example, another live vaccine.’

Nonetheless, BCG itself is far from perfect, especially since it does not protect against adult TB, with 1.4m people dying from the disease in 2019. Many immunologists have struggled to develop a new vaccine, and BCG remains the only approved TB vaccine. BCG itself remains somewhat mysterious. ‘We don’t know exactly how this vaccine protects,’ says Levy.

Live vaccines can give more durable protection. It’s not a shocker that the human immune system responds more profoundly to a live microbe than a dead one.
Ofer Levy a vaccinologist at Harvard Medical School, Boston, US.

One new TB vaccine strategy is based on proteins from the mycobacterium, but some worry that such a non-living vaccine might protect against TB, while throwing overboard benefits from live vaccines. Nor is there widespread recognition of these upsides. ‘It is not well recognised,’ admits Levy. ‘I think it’s either controversial or ignored.’ Yet the proposal has been gaining credibility. The World Health Organization, by 2014, viewed non-specific effects as ‘plausible and common’.

Microbiologist Carlos Martin at the University of Zaragoza, Spain, has developed a TB vaccine based on M. tuberculosis itself. Decades of research generated a live bacteria hobbled genetically by deleting genes implicated in virulence. The living vaccine, however, is otherwise the same as the mycobacteria that causes TB in humans. Phase 3 trials are under way with the vaccine – MTBVAC – in sub-Saharan Africa, comparing it with BCG for babies. The vaccine offers protection beyond TB in mouse studies. ‘We demonstrated that when you vaccinated the mice and then challenged them with Streptococcus pneumoniae, the vaccine offered protection,’ says Martin. In theory, the same should apply to babies, with MTBVAC offering protection against TB and – as a non-specific effect – against some fatal childhood infections.

Covid and BCG

In February 2020, researchers met at the Optimmunize conference in Cambridge, UK. The conference allowed the community to discuss how non-specific effects might suppress the coronavirus, with lockdowns commencing one week later, recalls Benn. This led to trials investigating the potential for existing live vaccines to mitigate Covid-19. Two years on, ‘a pattern emerging from these trials is that BCG reduces the risk significantly of Covid-19 in people who have a high degree of vulnerability,’ says Benn.

In November 2022, the community again met at the Optimmunize conference in Denmark. One notable study by Denise Faustman at Massachusetts General Hospital, US, looked at how multiple doses of BCG impacted Covid-19 in people with Type 1 diabetes. While 12.5% of those on placebo developed Covid-19, 1% of BCG-treated participants were confirmed with Covid-19 – chalking up a score of 92% efficacy. The BCG group ‘also displayed fewer infectious disease symptoms and lesser severity and fewer infectious disease events per patient, including Covid-19’, researchers reported (Cell Rep. Med., 2022, 3, 100728). A Greek trial similarly suggested a reduction in Covid-19 diagnoses amongst adults over 50 years with other illnesses when vaccinated with BCG (Front. Immunol., 2022, 13, 873067). This suggested that BCG could offer some protection against new pandemic viruses.

In contrast, a Dutch study reported that BCG jabs did not reduce absenteeism among healthcare workers (Clin. Microbiol. Infect., 2022, 28, 1278). Benn believes the immune boost from BCG benefits those who have vulnerable immune systems, whereas the vaccine might be neutral or increase the risk of symptoms in healthy adults. OPV also reportedly reduced the incidence of Covid-19 (Front. Immunol., 2022, 13, 907341).

Ironically, while a TB vaccine from the early vaccine era was being tested against Covid-19, the world’s attention was focused on mRNA vaccines. Widely administered Covid-19 vaccines were mRNA, viral vector, protein subunit or killed virus vaccines. Yet live vaccines are known to hold advantages. For example, the newest pertussis vaccine, based on a protein, protects against the disease but not transmission. Meanwhile, the older live pertussis vaccine hindered transmission of the bacteria. ‘Live vaccines can give more durable protection,’ says Levy. ‘It’s not a shocker that the human immune system responds more profoundly to a live microbe than a dead one.’

As another example, OPV offers robust protection from poliovirus infection and transmission, whereas inactivated polio vaccine prevents disease but allows people to transmit polio. ‘Usually, non-live vaccines do not give good protection against transmission,’ says Benn. While some laud mRNA vaccines, Benn worries they will not perform as well as a live vaccine. ‘A live Covid-19 vaccine, inhaled through the nose, will likely be much more efficient and better protect against infection and transmission,’ she says. A Lancet preprint from Benn and colleagues suggested that an overall mortality reduction was higher for adenovirus-vectored vaccines than for mRNA vaccines (SSRN, doi: 10.2139/ssrn.4072489).

Today, vaccine trials do not take account of illness or deaths from nontarget infectious disease, meaning non-specific effects go unrecorded. ‘It might be that in high-income countries we stopped using [adenovirus-vectored] vaccines due to adverse events, that are rare, but then missed out on beneficial nonspecific effects,’ says Benn. The Oxford-AstraZeneca vaccine used a live chimp virus, and a recent study indicated that this vaccine changed their innate immune response in people.

Benn argues that all vaccine trials should record all-cause mortality, and live vaccines should not be replaced by newer vaccines without taking overall impacts on public health into account. ‘Studies on Covid have supported the notion that non-specific effects may be relevant in vulnerable adults,’ says Benn, whereas previously most studies had involved children. There might even be intergenerational benefits from live vaccines, she adds, although this has been shown in animal studies only – meaning that vaccinating fathers and mothers benefitted offspring.

Epigenetic shifts

Most clinicians remain unfamiliar with nonspecific effects, yet the field was bolstered by an unexpected discovery. Immunologist Mihai Netea at Radboud University Medical Centre in the Netherlands serendipitously uncovered a mechanism by which BCG resets our immune system. While using BCG as a control vaccine, his lab observed strong immunological effects against microbes other than mycobacteria. Netea asked his PhD student to repeat the experiment, but BCG continued to activate white blood cells of the innate immune system – our frontline defences. He proposed in 2012 that BCG trains immune cells to swiftly tackle future microbial incursions.

The Dutch lab tested the effect of BCG by giving it prior to the yellow fever vaccine, a live weakened virus, and found the virus was substantially lower in those given BCG beforehand (Cell Host & Microbe, doi: 10.1016/j.chom.2017.12.010). Netea subsequently reported that BCG works by changing how the DNA of the immune cells are chemically packaged – epigenetic modifications – priming them to quickly target and eliminate the weakened yellow fever virus. Another study showed that BCG genetically reprograms stem cells in bone marrow that become innate immune cells – prepping them for a faster response to microbial incursions.

This would have been heretical 20 years ago, when it was assumed that innate immunity is not trained by encounters with pathogens. It now seems these cells are influenced by the microbes that they encounter. And live vaccines may be especially suited to mustering frontline defenders. ‘It shouldn’t surprise people that the innate immune system has memory features, because organisms such as plants and insects do not have T and B cells,’ says Levy, ‘yet it is unlikely they would have no way of adjusting to or remembering a prior infection.’

In the recent study of 10 volunteers, scientists in Dublin showed that people vaccinated with the AstraZeneca ChAdOx1 Covid-19 vaccine, which uses an adenovirus vector, had more white blood cells in their peripheral blood than beforehand, for up to three months after getting the jab (J. Clin. Invest., 2023, 133, e162581). ‘The data suggest this enhanced ability to respond to any infection may protect a person in the short term,’ explains study author Sharee Ann Basdeo, an immunologist at Trinity College Dublin, Ireland. Her group suggests this may also affect diseases linked to inflammation in some predisposed people after vaccination. This is the first evidence, says Basdeo, that adenoviral vaccines can promote trained immunity in humans.

‘Some people look at BCG and say we don’t make vaccines like that anymore, it’s old school,’ says Levy. ‘But there are important lessons to be learnt, because our subunit vaccines with all our sophisticated protein and adjuvant science still cannot match up to BCG, at least in newborns.’ Even if live vaccines themselves are eventually replaced, Levy says lessons must be learnt from them. ‘Don’t treat BCG as an irrelevant dinosaur, because it is saving lives in more ways than one.’

Allergy effects

The potential benefits of live vaccines may not stop at infectious disease. Allergic conditions such as asthma can be triggered by a type of immune reaction centered on Th2 – T helper 2 cells. This musters IgE antibodies and immune elements such as mast cells implicated in allergies. There have been many studies demonstrating BCG protecting against allergies in mice, by reconfiguring the response to Th1. And for more than two decades researchers wondered if the same holds true for people. Immunologist Nigel Curtis at the Murdoch Children’s Research Institute in Victoria, Australia, is investigating the immune response to the BCG vaccine. At the end of 2022, Curtis, along with epidemiologist Christine Stabell Benn in Denmark and others analysed three separate trials of children randomised to receive BCG early in life. They concluded that BCG prevents some eczema, with the benefit being greater in boys. Overall, BCG cut the risk of eczema in early life by 11% (Dermatitis, 2022, 33, S3).

Image credit: KATERYNA KON/SCIENCE PHOTO LIBRARY