The second coming: The comeback of the live vaccines

The downside is that many live vaccines have strong reactogenicity, which can lead to severe side effects in some recipients, a drawback that can also affect vaccines based on killed pathogens, such as the original vaccine for whooping cough, an inactivated, whole‐cell preparation of Bordetella pertussis. “At the time, when you looked at a database that collected vaccine side effects, the majority were from the whole‐cell pertussis vaccine”, Leitner commented, adding that over time, the tolerance for even relatively benign side effects decreased.

Moreover, live viruses can, in rare cases, mutate to escape their attenuation shackles. This happened with the Sabin oral polio vaccine (OPV), first introduced in 1961. It sometimes spreads in populations where vaccination is low and it can regain transmissibility and virulence of the wild‐type virus. As incidence of wild poliovirus fell due to vaccination, OPV came under the spotlight for causing paralytic disease, although incidence is extremely low. Nonetheless, live OPV vaccination is scheduled to stop in 2024, replaced by inactivated polio vaccine (iPV).

This explains, in part, the trend towards protein subunit vaccines. These are prepared from proteins or glycoproteins derived from pathogens and boast more targeted aim without causing disease and with fewer side effects. They are not as immune stimulatory, though, so the immune system requires a poke from adjuvants. For decades, aluminium salts (alum) were the only adjuvant used in vaccines; how alum works is still not entirely understood, but it attracts immune cells to an injection site and promotes an antibody response. Whole and subunit vaccines work well in tutoring the adaptive immune cells with its B cells and antibodies, but the innate arm of the immune response is triggered far more by live than non‐live vaccines. The trick is to get the same response out of subunit vaccines, partly by better understanding live pathogen effects. “The more we learn about attenuated vaccines the more we can translate those lessons into subunit vaccines, to get the best of both worlds. Safe and effective vaccines”, Leitner commented.

Meanwhile, there has been accruing evidence that live vaccines exert additional non‐specific health effects. Peter Aaby, an anthropologist who built a health surveillance system in Guinea‐Bissau, reported that measles vaccination decreased childhood mortality above and beyond measles prevention. These and other observations report a pattern whereby live vaccines such as for smallpox, BCG, measles and polio all increase resistance to infections unrelated to the target disease. “We saw that children who got BCG had almost half the mortality rates as those who did not”, said epidemiologist Christine Stabell Benn at the University of Southern Denmark, who has carried out studies with her spouse Aaby in Guinea‐Bissau and in Denmark.

When they compared children with and without a BCG scar (signifying a correctly administered vaccine), they discovered 40% less mortality amongst those with a scar. Danish adults who had received smallpox and BCG vaccines at school entry have a more than 40% reduced risk of dying up to the age of 45 by infectious disease (Rieckmann et al, 2017). The benefits of BCG in particular have inspired clinical trials into whether this vaccine can protect or ameliorate against SARS‐CoV‐2 infection.

“The live vaccines all seem to prime the immune system and protect against sepsis, respiratory infections and various other [infectious diseases]”, noted Katie Flanagan, an infectious disease researcher at the University of Tasmania and Launceston General Hospital in Tasmania. “MMR vaccine seems to have the same effect”. The priming mechanism was unknown when epidemiologists such as Benn first proposed it. The WHO, however, was sufficiently convinced in 2014 to describe non‐specific effects as “plausible and common”.

Immunologist Mihai Netea at Radboud University Medical Centre in the Netherlands is credited with uncovering a mechanism to explain benefits from live vaccines in terms of non‐target disease. He proposed in 2012 that BCG vaccination trains the innate immune system, tweaking progenitor cells epigenetically to put them at a higher state of readiness. “Stem cells in the bone marrow after BCG are able to produce more cells that are more effective for host defense”, Netea explained. He tested the effect of BCG on the mild infection induced by attenuated yellow fever vaccine. People vaccinated with BCG had much lower number of yellow fever vaccine virus in their blood (Arts et al, 2018). “They recruit immune cells to the site of the infection quicker and those cells are better at killing and eliminating the virus”, Netea explained. The notion of innate immune memory was once controversial, but it is now widely accepted. “BCG seems to be able to change how DNA is organised in terms of epigenetics, or chemical modifications, and prime it to be more responsive to subsequent unrelated infections”, explained David Lynn, director of systems biology at the South Australian Health & Medical Research Institute in Adelaide, Australia. Netea and Benn recently described how BCG vaccination rewires bone marrow stem cells and results in higher neutrophil counts within days in infants (Cirovic et al, 2020).

Aaby and Benn therefore argue vehemently against stopping vaccinations with live vaccines, noting that OPV also delivers non‐specific benefits. Aaby estimates that half the 40% fall in childhood mortality in Guinea‐Bissau is due to polio vaccination campaigns. “Withdrawing it is probably going to lead to more deaths in high mortality settings”, Flanagan agreed. She and others warned in March 2016 in the Lancet that replacing OPV with inactivated polio vaccine could translate into 4,000 deaths for each case of polio linked to OPV and might cause more than 300,000 additional deaths a year (Fish et al, 2016). Benn says that results from collaborators in Bangladesh, Uganda and Burkina Faso are supporting oral polio vaccine having strong beneficial effects and described the WHO plan to phase out oral polio vaccine in 2024 as a huge mistake: “we are yelling the best we can that this may be a terrible idea for Africa”. Aaby, Benn, Lynn and Flanagan are all members of the Optimmunize consortium (www.bandim.org/optimmunize), which aims to raise awareness of the non‐specific effects of vaccines and sex differences in vaccine effects.

A growing number of immunologists and vaccine scientists have joined their concerns also about non‐live vaccines such as the DTP (diphtheria, tetanus and pertussis) vaccine. Members of the Optimmunize consortium suggested that non‐live vaccines increase all‐cause mortality from pneumonia and sepsis especially in girls (Aaby et al, 2020). Aaby reported that male/female mortality ratio rose after DTP vaccination in Asia and Africa in nine studies reviewed, while in six randomised trials of early measles vaccine, female but not male mortality was increased if DTP was likely to be given after measles vaccine (Aaby et al, 2012). The authors also noted how seven studies showed negative effects on survival from DTP, in contrast to beneficial effects from BCG and measles vaccine.

While live vaccines prime the immune system, killed vaccines can have the opposite effect, said Flanagan, who ran a vaccine research programme in Gambia for seven years: “They increase susceptibility to infection and worsen outcomes”. She discovered that DTP can depress innate immunity and switch off T‐cell immunity, but only in female not male infants. The live measles vaccine did not. Moreover, when BCG, OPV, DTP and measles vaccine were introduced into the global vaccine programme in the 1970s, the overall effect on survival was not examined in randomised control trials. It was considered enough to show that the vaccine generated a specific immune response or protection against their target infection.

Most early animal studies and human trials did not analyse sex differences in vaccine response either. “Vaccine trials were conducted in men, because of the fear of women being pregnant or getting pregnant”, Flanagan explained. Yet, sex matters. “Women and men do not respond in the same way to infectious challenge. Men are more likely to die from sepsis for example”, Flanagan said. “The way the immune system is programmed in the two sexes is different”. Women tend to have stronger innate and adaptive responses to infection, perhaps as an evolutionary mechanism to clear infection rapidly and look after children, Flanagan suggests, while men are more likely to succumb to many infections. One study found that females given a half dose of standard flu vaccine had the same antibody levels as males given the standard dose. Recent research also indicates that females benefit more from the non‐specific effects of measles vaccine, but do worse following DTP vaccination. Hormone exerts an influence and there are many immune response genes on the X chromosome, while not so many on the Y chromosome. “Not infrequently, male and females respond in opposite directions [to vaccines]. You can miss responses by analysing them together”, Flanagan warned.

The Optimmunize group sent evidence to the WHO on sex differences and on non‐live vaccines. “We consistently find that non‐live vaccines are associated with overall increase in female mortality”, noted Benn. “They have swept it under the carpet”. The WHO notes that the evidence for raised mortality is observational. But it would be unethical to withhold vaccines from children in Africa for randomised controlled trials. Flanagan is indeed adamant that vaccinating against diphtheria, tetanus and pertussis must continue, but argues that we need to understand better what vaccines are doing to the immune system and how we can overcome any negative effects.

Fortunately, there is a potential solution at hand. Flanagan is researching the molecular mechanisms behind apparent suppression of the immune system in females following vaccination with non‐live vaccines such as DTP. She says that if you give a live vaccine with an inactivated vaccine, then the negative effects can be overcome. A 2017 report among US children found lower risk of infectious disease hospitalisations when the last vaccine received was live rather than inactivated (Bardenheimer et al, 2017). Flanagan's research in Africa found a similar benefit. “If you give DTP vaccine in high‐mortality settings, you are more likely to get infections and die from infections if you are female, but if you give the live vaccines with it, the negative effect is lost”, she said.

Flanagan commented that the WHO struggles to acknowledge that a widely distributed vaccine might have negative impacts. Moreover, public health policy change will require strong evidence. “With DTP, [the WHO] don't think there is sufficient evidence [for negative effects]”, added Flanagan. “I think the evidence is quite compelling and very consistent, but it isn't based on randomised controlled trials and they said it is not ethical to do them”. Not everyone views the female safety signal as conclusive though. “I cannot decide myself”, Netea said. “It seems there is an effect, but how strong it is I cannot say”. Immunologist Kingston Mills in Trinity College Dublin, Ireland, said that in his view the evidence for higher all‐cause mortality in females after DTP is not strong enough to support changes to vaccine schedules.

Talking publicly about the downsides or raised mortality from a vaccine such as DTP is seen by some researchers as dicey as this might bolster anti‐vaccination campaigners. “It is a controversial area”, said Ofer Levy, director of the precision medicines programme at Boston Children's Hospital. “It has become difficult to have certain conversations because of the fear of how it will be picked up and understood by the public”. Benn sympathised with the WHO and its attempts to keep the message on vaccines straightforward, but said it is critical to discuss how existing vaccines can be improved. “Authorities shouldn't be afraid of the anti‐vaxxers so much that they say vaccines are all good and we don't need to discuss them”, she said.

A strategy the NIAID is pursuing is to combine killed or subunit vaccines with new, improved adjuvants. “We try to replicate with adjuvants the live vaccines as much as possible. We are now learning more and more how hard that is”, Leitner said. More basic research in immunology helps, such as understanding how adjuvants might trigger critical switches in the innate immune system called Toll‐like receptors (TLRs). Adjuvants that stimulate the right TLR responses could circumvent some of the negative effects of non‐live vaccines. Pertussis offers a cautionary tale. Whole‐cell pertussis vaccine was withdrawn and replaced by an acellular version in Western countries decades ago, partly because of side effects such as redness at the site of injection. The whole‐cell pertussis vaccine fell out of favour, there were vaccine‐related lawsuits in the USA and manufacturers stopped producing it in the 1980s.

The newer pertussis component of DTP relies on a few antigens, but it is suboptimal. “The whole cell pertussis vaccine was great, very effective. Cases dropped to almost zero when it was introduced”, said Leitner. The new vaccine prevents whooping cough, but it does not prevent infection and colonisation by B. pertussis. For Levy, the changeover has been a mixed bag: “We reduced the reactogenicity with the pertussis vaccine, which was problematic, but at the same time it was associated with reduced efficacy. We need multiple boosters”.

One result has been a rise in pertussis in many countries. “We now have people who are infected, but don't have the disease, and are able to transmit the organisms to naiive individuals”, explained Camille Locht, research director at the French National Institute of Health and Medical Research (Inserm) in Lille, France. In countries with high vaccination rates, cases of pertussis in adults and adolescents are again on the rise. There have also been indications that pertussis toxins may exacerbate coeliac or other inflammatory diseases, such as Alzheimer's, so such infections cannot be dismissed as harmless.

Locht has worked for 15 years to develop a solution. His live BPZE1 strain of Bordetella pertussis has the genes for three toxins modified to eliminate toxicity, including pertussis toxin. Nasal administration protected baboons after a single nasal administration and data for the phase I trial will shortly be published (Locht et al, 2017). A phase IIa study is underway in the USA. “This vaccine mimics the infection, so the second dose should not take”, Locht explained. “In mice, monkeys or humans, you see that [BPZE1] persists and then disappears within about two to four weeks. It induces sustained immune responses both mucosal and systemically, which is exactly what we want”.

Trials are also underway for a new live polio vaccine. The original Sabin oral polio vaccine had its ability to infect the central nervous system hobbled when it was passed through monkey kidney cells but it is sometimes able to regain its original virulence. Virologist Raul Andino at the University of California, San Francisco, isolated and analysed these problem viruses and identified three critical gatekeeper mutations needed for the virus to escape attenuation. Developing a new live vaccine candidate, he changed the poliovirus RNA to make it far more stable and altered the enzyme involved in its replication so that it generated fewer mutations and less recombination events (Yeh et al, 2020). A phase 2 trial of this novel oral polio type 2 (nOPV2) vaccine in infants and children aged 1 to 5 years is underway in Panama. Polio eradication could finally be pushed over the finish line using this modified live poliovirus.

Changing vaccine recommendations is not a simple matter for an organisation like the WHO though. Optimmunize members advocate tweaking vaccine regimens so that a live vaccine is given with killed or subunit vaccines. “Switching the order of certain vaccines so that people end with getting a live vaccine, if it would diminish side effects, is not such a big change. It could be done”, Netea said. Others are at pains to stress vaccines overall benefits. “People might misinterpret and think you must not get a DTP vaccine for example, but you clearly need to have this”, Flanagan said. It massively reduces neonatal tetanus and pertussis. She and others instead evangelise for a revolution in how vaccines are perceived. “People need to understand that vaccines do more to the immune system that just give you protection against a specific disease”, Flanagan concluded.