In less than 50 years, the industrial production and use of live attenuated vaccines, which contain a living pathogen treated to be less virulent, has led to an exceptional reduction in morbidity and mortality due to infections in the world.
Vaccines of this type have been used successfully in many mass prevention campaigns: the tuberculosis vaccine (the famous Bacillus Calmette–Guérin or BCG vaccine, in 1921), Sabin’s oral polio vaccine (OPV, 1962) or the combined measles, rubella and mumps vaccine (MMR II, 1971) are all live attenuated vaccines.
However, we still have a long way to go before fully understanding the protective effects of this type of vaccine. Recent studies have revealed that they generate not only specific protection against the infectious agents against which they were developed, but also non-specific protection. This calls into question the fundamentals of the current vaccine paradigm, and also has important implications for vaccine policy in general.
The basics
Live attenuated vaccines contain infectious agents (viruses or bacteria) whose virulence has been weakened by a series of treatments. One method is to cultivate the virus for which a vaccine is to be developed for a long period of time on cells of another species. This makes it multiply less effectively in humans but retain its immunising effect. The OPV was designed by this procedure.
Even when a virus is attenuated, however, its use is not without risk, especially in individuals whose immune system isn’t yet fully developed or has been weakened (newborns, pregnant women, the elderly, etc.).
As knowledge of immunology progressed, second-generation vaccines, called subunit vaccines, were developed to address this problem. They were developed based on the paradigm of the specificity of acquired immunity to infections.
Specificity of acquired immunity
Throughout the 20th century it was widely accepted that after a natural infection or vaccination, our body develops specific immunity to the antigens expressed by infectious agents. These antigens – which may be composed of proteins, sugars or lipids of the pathogen – are recognised by lymphocytes, the body’s specialized immune cells.
Each lymphocyte has the exceptional ability to recognise one given antigen. Because the human immune system produces an immense number of lymphocytes (there are over 108 in humans), it can potentially recognise all possible antigens.
After vaccination or a natural infection, the pathogen triggers the proliferation of lymphocytes that recognise its antigens and constitute a long-lasting immune “memory”. When the pathogen is encountered again, these cells respond and neutralise the pathogen before it damages the body.
This paradigm has served as the conceptual basis for the development of new vaccine strategies involving subunit vaccines, which contain only the pathogen’s “dominant” (i.e., most expressed and least variable) antigens and an adjuvant, which stimulates the immune system. Unlike live attenuated vaccines, subunit vaccines do not contain living components and are therefore considered safe for at-risk individuals.
Live vaccines also confer non-specific immunity
However, the paradigm of specific acquired immunity against antigens of the infectious agent has been questioned more recently. Studies have shown that live attenuated vaccines can provide, in addition to immunity against the targeted infectious agent, immunity against unrelated pathogens. The vaccinated individual therefore benefits from non-specific protective immunity.
For example, individuals vaccinated against smallpox are not only protected against smallpox but are also statistically less susceptible to infectious diseases such as measles, scarlet fever, whooping cough and syphilis compared to their unvaccinated counterparts. The same phenomenon has been reported for the BCG, OPV and measles vaccines.
The persistence of a pathogen following natural infection, even at very low levels, has also been shown to possibly affect the ability of the immune system to respond to unrelated infectious agents. For example, chronic infection with the herpes virus may confer protection against Listeria monocytogenes and Yersinia pestis bacteria.
Alongside these results, numerous studies have shown that our microbiota (all bacteria, fungi and viruses that live in symbiosis with our body) also contributes to the control of infections. For example, it can compete with pathogens to acquire nutrients or induce an immune repertoire that can cross-react to recognise and neutralise certain pathogens.
All these observations argue in favour of looking at acquired immunity in a novel way.
Toward a new paradigm of acquired immunity?
Contrary to accepted doctrine, it seems that a non-negligible part of acquired immunity is not specific to the antigens expressed by pathogens encountered previously. This acquired protection may depend on the immune history, chronic infections and microbiota composition. It is thought to be strongly influenced by the individual’s experience and way of life and thus vary widely.
From an evolutionary point of view, partially non-specific immune mechanisms seems very advantageous. Among other things, it could help fight against certain highly polymorphic and rapidly evolving pathogens. Furthermore, individual variability would increase the resistance of a population to epidemics.
This new paradigm could have important practical implications for vaccination strategies. Attenuated live vaccines are well known to induce non-specific protective effects. Should we then continue to use them even if their respective target diseases are now rare or have been eliminated? They could indeed have important beneficial effects for populations by protecting them against other infectious agents.
Before restricting the use of a live attenuated vaccine, it would therefore be wise to quantify its non-specific beneficial effects. Unfortunately, such a precautionary principle is difficult to apply in the current climate of mistrust of vaccines.
When pathogens adapt
Another implication of this discovery is that, for safety reasons, modern vaccination strategies focus on the development and use of adjuvanted subunit vaccines. However, this approach neglects the adaptive capacity of some pathogens whose antigenic composition is very complex and fluctuating.
This is the case of small RNA viruses, such as HIV, which have a limited number of genes but produce an extraordinarily high number of variants in the host in a very short period. Some bacteria can also evolve during an infection. A pathogen capable of evolving rapidly is likely to escape the immune system if the selection pressure is put on its most specific and stable form. The development of resistance to some subunit vaccines has recently been documented.
Unlike subunit vaccines, live attenuated vaccines induce not only specific protection against a wide range of antigens, but also non-specific protection. They are therefore potentially able to cope better with infectious agents able to evolve rapidly. Consequently, the replacement of first-generation live attenuated vaccines with subunit vaccines should be based on the specific and non-specific benefits of each vaccine. The World Health Organization has recognized the importance of the non-specific effects of vaccines and recommended that research be continued in this new direction.