What makes a good vaccine?

To create an ideal vaccine, we need to carefully consider the history of this revolutionary medical technique say Gary Entrican and Lee Innes

VACCINATION to protect against infectious diseases has been in the public eye more in the past ten years than any other time previously. This has been fuelled largely by the debate around safety concerns of the combined measles, mumps and rubella (MMR) vaccine for children in relation to autism, a link for which there is no concrete supportive evidence.

With hindsight, we now know that the reported incidence of autism has continued to rise as the uptake of MMR has decreased. The inevitable consequence is the prevalence of measles has increased in the UK. This highlights an underlying principle of vaccination that came to the forefront with MMR:  what is the benefit of a vaccine versus the risk of taking, or not taking it? When one lives in a country with good healthcare and access to vaccines for common diseases, it can be easy to forget how devastating an infection such as measles can be in infants. Measles can kill.

What tips the balance of benefit versus risk, and what other factors should we take into account when designing new vaccines to control infectious diseases in humans and animals? To begin to answer this question we need to go back to the history of vaccination and learn from lessons of the past.

The father of modern vaccination is Edward Jenner, a doctor who lived in Gloucestershire in the late 18th century. This was an era when smallpox was among the most feared diseases of humans. Smallpox is caused by the variola virus. The disease is typified by pustules over the body that are full of infectious virus, putting anyone in contact with an infected person at high risk. Up to one in three people who contracted smallpox died, and those who survived usually had characteristic pock marks on their skin to indicate previous infection. It had been recognised for hundreds of years that anyone who survived smallpox would not have the disease again, a phenomenon we now conceptualise as ‘immunological memory’. Jenner recognised something else in addition. He noticed that milkmaids had clear skin and did not suffer from smallpox. Instead, they had the milder disease cowpox, which they had contracted from the udders of cows they were milking. Jenner therefore hypothesised that cowpox would protect against smallpox.

Jenner tested his hypothesis by an experiment that would be ethically unacceptable today. In 1796 he scratched the pus from a cowpox pustule into the arm of an eight year old boy and later injected the boy with smallpox pus. The boy survived but Jenner’s initial report was met with scepticism. He repeated the experiment several times, all with the same outcome, and the principle of vaccination was established, derived from vacca (cow). Interestingly, even given the hazard associated with smallpox infection, the perceived safety risk of the cowpox vaccine was that recipients would grow cow parts from their bodies as a result of the injection. This may seem ridiculous today but demonstrates that knowledge and education are important components of any vaccination strategy if it is to be accepted.

Jenner’s pioneering experiment led to the global eradication of smallpox in 1979. In addition to the efficacy of the vaccine, one of the reasons that smallpox could be eradicated was that there was no animal reservoir for the virus. Once a policy was put in place to vaccinate humans, the virus could not survive. His achievements are honoured in The Jenner Museum in Gloucestershire.

There are, of course, other infections that humans can contract from animals

(termed ‘zoonotic infections’) such as toxoplasmosis and salmonellosis. Some of these infections can be acquired from companion animals; others may derive from livestock and be a concern for food safety. Vaccination of animals can reduce the risk of human infections, but vaccines are also required for animal health and welfare in their own right. The requirements for animal vaccines are not necessarily the same as those required for humans.

 In all cases a vaccine should be safe and efficacious, but what about the duration of immunological memory? Humans might want their vaccine to stimulate memory that lasts 10 years or more. This won’t be required for animals that are kept for meat production since they may only have a lifespan of several months. The cost of vaccinating livestock animals is also an important factor; there comes a point when the cost of the vaccine will not be economically viable. Another important feature is the practicality of delivering the vaccine. Vaccinating large numbers of animals can be problematic, therefore finding safe and efficient routes of delivery e.g. oral is highly desirable.

Infectious disease remains one of the major challenges we continue to face today and the focus of much research effort is in developing strategies to control and prevent disease of both humans and animals. Developing effective vaccines is highly desirable as they will prevent disease and limit host reservoirs for the pathogens to infect and multiply within. The Moredun Research Institute, based just outside Edinburgh in Scotland, has a worldwide reputation for the development of vaccines to help prevent and control infectious diseases of livestock and for zoonotic diseases that may be transmitted from animals to people. Originally established by Scottish farmers in 1920, to help find solutions to control disease in their livestock, Moredun has gone on to develop several highly successful vaccines to help combat pneumonia, reproductive diseases, gastrointestinal disease and vaccines to protect against some important zoonotic pathogens, such as Toxoplasma.

The tiny protozoan parasite Toxoplasma gondii (image1) is transmitted by cats and

can infect animals and people. It can cause severe disease in the developing foetus if the infection occurs during pregnancy, which may result in death of the foetus or birth of children with brain damage, blindness and/or hearing problems. The parasite invades and multiplies within the host cells and scientists at Moredun studied how the immune system is able to attack the parasitized host cells and successfully inhibit multiplication of the parasite. They used this knowledge to develop a vaccine strategy to help prevent toxoplasmosis in pregnant sheep.

This research showed that is important to understand how infectious agents invade and multiply within the host and how the immune system of the host defends itself against the microbial invaders and then use this knowledge to develop a vaccine strategy. The vaccination strategy adopted may be very different for each infectious agent and some will prove very difficult to achieve.

A difficult group of organisms to control by vaccination are parasitic worms. These organisms cause major production losses in farm livestock worldwide and are a major cause of human disease in many developing and tropical countries. One of the main reasons for the difficulty in developing vaccines against parasitic worms is that they have evolved very sophisticated methods to evade our immune responses. An example of this is a parasite called, Haemonchus contortus (image 2), commonly known as the barber’s pole worm. This blood-sucking parasite is one of world’s most important pathogens of sheep and goats.

The worm feeds by sucking blood from its host and scientists at Moredun have used this knowledge to target their vaccine approach to attack the gut of the worm. When the worm feeds it will take in specific antibodies generated by the vaccine and these will attack the worm from the inside out. This vaccine is currently being tested for its ability to protect against these blood-sucking parasites in Australia, South Africa and Brazil.

While Jenner established the principle of vaccination, the exact approach he took for smallpox clearly does not work for all infections. We have vaccines for human diseases such as polio, diphtheria, tetanus, hepatitis, measles mumps and rubella, but vaccines for the major killers such as malaria and AIDS remain elusive.   

As we understand more about the pathogens, how they invade and multiply within hosts and how the immune system of the host can act to defend itself against the microbial invaders, we can use this knowledge to design effective vaccination strategies. One strategy will not be effective for all pathogens and we will need to tailor our approach by understanding the often complex host-pathogen relationship. Pathogens are constantly evolving and there are considerable challenges for scientists in developing safe and effective vaccines.  However as most of us would agree that prevention is better than cure, vaccination as a disease control strategy is a goal well worth pursuing.