Over two hundred years ago, Edward Jenner published his booklet An Inquiry into the Causes and Effects of the Variolae Vaccinae in which he described his successful attempt at inoculation–intentionally introducing an infective agent to a body. Jenner exposed a young boy to cowpox and subsequently observed that the boy was protected from a much more deadly viral cousin: smallpox. He called this observed protection vaccination.

Jenner’s discovery would eventually lead to the global eradication of smallpox by 1977. But this incredible success is unfortunately an exception rather than the rule when it came to eradicating infectious diseases. For example, the Global Malaria Eradication Program of 1955 failed to eradicate the disease from the most susceptible communities in sub-Saharan Africa due to a combination of technical challenges and the resistance mechanisms of the malaria parasite. Similar frustrations are ongoing with polio and dengue fever.

But just because vaccines have not systematically eradicated every infectious disease known to man does not imply that they have not had an overwhelmingly positive impact on human history. In fact, it is estimated that vaccines prevent 2-3 million deaths per year.

These numbers should reassure us of the incredible potential of vaccines to save lives, while also encouraging us to consider methods of improving vaccine delivery and effectiveness to prevent and hopefully eradicate the many illnesses still plaguing global populations.

While public health programs strive to improve access as well as support complementary programs such as mosquito nets, another area of innovation is the biological mechanism of the vaccines themselves.

Edward Jenner’s discovery was most closely related to what is today known as a live, attenuated vaccine (LAV). Live, attenuated vaccines are derived from a real virus (or other pathogenic microorganisms) but are passed through a series of hosts–such as embryonated eggs–until they are weakened to the point of no longer posing a threat of infection to humans. When an individual is exposed to a virus, their body mounts an immune response that fights the infection and results in the production of protective antibodies. These antibodies will more quickly recognize a virus should that same individual ever be infected again–this is basically the same process that makes it so you can’t catch chickenpox more than once. Live, attenuated viruses offer a safer method of introducing a virus to an individual’s immune system to stimulate the production of those antibodies without the risk of the individual actually getting ill. Jenner similarly introduced a milder form of smallpox, although he didn’t intentionally weaken the smallpox virus, as would be done with a LAV today.

While LAVs have demonstrated huge success–the WHO recommended vaccines for tuberculosis, polio, and measles are all live, attenuated–there are some safety limitations that have and should continue to encourage innovation in vaccine delivery. Because LAVs are still live microorganisms, the delivered vaccine can hypothetically revert to a pathogenic form and cause disease in vaccinated individuals, although this only happens in extremely rare cases. Additionally, immunocompromised individuals may not be able to mount a substantial enough immune response to receive even the weakened form of the virus. Finally, there is a greater risk of contamination of a live vaccine during development processes.

The complement of LAVs are Inactivated Vaccines, which are made from whole microorganisms that have been killed through physical and/or chemical processes. Because these vaccines are dead, they are incapable of reverting to an infectious form (like LAVs). However, with this decreased risk comes decreased effectiveness: inactivated vaccines often require multiple boosters to maintain resistance, and are sometimes poor at facilitating immune responses at all.

While LAVs and Inactivated Vaccines have made incredible progress for public health, scientists are not settling. So what kind of innovation is going on in vaccines today? There are a number of exciting new vaccine modalities that have the potential to revolutionize the way we prepare our immune systems not only for the threat of infectious diseases but potentially even broader disease areas.

Virus-Like Particles

Virus-like particles are basically exactly what they sound like: structural proteins that look like viruses, but aren’t quite. These particles are composed of structural/capsid proteins derived from real viruses but without any accompanying genetic material. This lack of genetic material means that the virus cannot infect individuals or reproduce itself–in other words, it lacks all the harmful bits of a typical virus.

Virus-like particles can still be effective because your immune system recognizes the surface proteins on the particle which match the real version of the virus, and so your immune system mounts an antibody response similar to what it would do in a real infection. The vaccination effect is extremely strong but without the risk of reversion to a live virus.

Not only do VLPs offer a safer and more effective alternative to LAVs and Inactivated Vaccines, but they are cheaper and faster to produce.

‍One study found that the development and preparation of a VLP vaccine in response to an influenza outbreak took only 8 weeks, compared to 5 months for a traditional attenuated vaccine.

These particles can additionally be produced through recombination of the viral DNA with another cell, such as yeast or E. coli: the yeast’s own cellular machinery renders the components of the proteins that can then assemble into VLPs. Harnessing yeast to grow the particles reduces operating costs compared to traditional vaccine manufacturing, which also has important implications for rapid response times to sudden outbreaks or epidemics. ‍

A number of VLP vaccines have already been approved for diseases including Human Papilloma Virus, Hepatitis B, and Malaria.

Nucleic Acid Vaccines

Nucleic acid vaccines include DNA and mRNA vaccines. DNA vaccines are delivered in the form of plasmids–circular rings of viral DNA that can be delivered like a typical vaccine. The plasmids end up transfected into host cells resulting in your body’s own production of viral proteins, against which the immune system mounts a response. Like VLPs, DNA vaccines can result in robust immunity with a decreased risk of side effects, while also being cheaper and more stable than traditional vaccines. This technology is still early in development and has yet to be approved in humans, although it has demonstrated efficacy for a variety of diseases in animals.

mRNA vaccines are similar to plasmid DNA vaccines in that they result in the self-production of viral proteins inside the vaccinated individual. mRNA is the transcript that tells a cell to produce proteins–if that transcript codes for viral proteins, the host will produce proteins against which the immune system can mount a response. mRNA vaccines are believed to have a number of benefits over DNA vaccines, including their smaller size and the fact that, unlike DNA, they do not integrate with the host’s cells. These vaccines are similarly early in production, but a number of companies, particularly Moderna Therapeutics, are demonstrating positive clinical data.

Cancer Vaccines

It would be remiss in discussing vaccine innovation to not mention cancer vaccines. Cancer vaccines can be preventative, protecting against viruses that can lead to cancer, such as the HPV vaccine Gardasil. But they can also be therapeutic, delivered once an individual has already contracted cancer, to help the immune system produce cells that can better recognize and attack the cancer. The first approved therapeutic cancer vaccine was Sipuleucel-T for advanced prostate cancer. Though Sipuleucel-T demonstrated efficacy, the majority of therapeutic vaccines have been ineffective compared to other immunotherapies, such as immune checkpoint inhibitors.

There has been renewed interest in cancer vaccines, however, and work is ongoing to identify tumor signals that elicit strong, targeted immune responses, as well as mutated proteins (neoantigens) that often arise in cancers and could offer similar targets.

Conclusion

Vaccines have had a profoundly positive impact on recent human history and save millions of lives every year. But the fight against infectious diseases is far from over, and the technologies developed to improve vaccine safety and efficacy may very well be translatable to other disease areas.