The Growth of Vaccines Beyond Infectious Disease

Vaccination for infectious diseases saves two to three million lives a year worldwide, according to the World Health Organization (WHO). Following the implementation of national programmes for immunization in the 1960s and beyond, many of the diseases that caused the majority of childhood deaths, such as diphtheria and polio, virtually disappeared. ^[1] The story of modern vaccines began with smallpox and Edward Jenner, but the history goes back even further.

The story of the smallpox vaccine

Humans have lived with infectious diseases for millions of years, with modern infections emerging around 11,000 years ago with the rise of agriculture. ^[2] Smallpox is likely to have appeared appeared in Africa around 10,000 years ago, and spread across Asia, Europe and the Americas. ^[3] During the 20th century alone, smallpox killed 300-500 million people worldwide.^[4]

Attempts to vaccinate against smallpox seem to have begun in China and India as long ago as the mid-1500s or earlier. Known as variolation, the process involved deliberate infection with smallpox to trigger a mild form of the disease, to protect people against the deadly infection. While it reduced fatality rates, it unsurprisingly carried risks. ^[5]

After observations that people who developed cowpox were immune to smallpox, inoculation with material from cowpox lesions began in the mid-1700s. This was formalised by Edward Jenner in 1796 when he inoculated 8-year-old James Phipps with material from cowpox lesions from Sarah Nelms, a milkmaid. By the 1800s, the process of vaccination (from the Latin word vacca for cow) spread across Europe and the US. 

While vaccines still play a vital role in infectious disease, the knowledge and techniques behind decades of research has allowed vaccination techniques to be applied in other areas of medicine. 

Cancer vaccines: Therapeutic

Cancer immunotherapies, also known as cancer vaccines, are the most advanced vaccines outside of infectious disease. These teach the body's own immune system to recognise tumour-associated antigens on the tumour cell's surface and attack and destroy them. The main types of cancer vaccines are: ^[6]

● Made from the patient's own cancer cells or dendritic cells (autologous)

● Made from tumour-associated antigens found on the cells of certain types of cancer (allogeneic) 

o Approaches include DNA, RNA/mRNA, protein/peptide and viral vector vaccines. 

The concept of immunotherapy to kill cancer cells goes back to 1893, and the only cancer vaccine to be approved in the US (2010) and Europe (2014) so far was Dendreon Pharmaceuticals' sipuleucel-T (Provenge), indicated for the treatment of metastatic, asymptomatic or minimally symptomatic, metastatic castrate-resistant hormone-refractory prostate cancer (HRPC). The costs behind the production, and the issues around reimbursement, unfortunately led to the collapse of Dendreon and the slowdown in cancer vaccine research. ^[7-9] 

Therapeutic cancer vaccines are in development for a wide range of indications, including: ^[9-11]

● Breast cancer

● Cervical cancer

● Chronic lymphocytic leukaemia

● Melanoma

● Non-small cell lung cancer

● Ovarian cancer

● Pancreatic ductal adenocarcinoma (PDAC)

Cancer treatments based on oncolytic viruses (viruses that attack cancer cells) can also be described as cancer vaccines. Amgen's talimogene laherparepvec, also known as T-VEC, or Imlygic, was the first oncolytic virus therapy to be approved worldwide, and is used to treat metastatic melanoma that cannot be surgically removed. ^{[6, 12]}

Cancer vaccines: prophylactic

While technically a vaccine against a virus, the herpes papillomavirus (HPV) vaccine plays a vital role in cancer prevention. HPV was first linked with cervical cancer in 1983, and the first HPV vaccine, Merck & Co's Gardasil, was launched in 2006. As well as reducing the risk of cervical cancer, HPV vaccines can also cut the incidence of vaginal, vulvar, penile, anal and certain mouth and throat cancers. ^{[13, 14]} A study in Scotland that tracked women born between 1988 and 1996 who were fully vaccinated against HPV aged 12 and 13 showed no cases of cervical cancer, confirming the benefit of getting the vaccine before the age of 14. In those who were fully vaccinated between the ages of 14 and 22, the rates of cervical cancer were two and a half times lower than in unvaccinated women. ^{[15, 16]}

There are other preventive cancer vaccines in development. Scientists from the University of Oxford, the Francis Crick Institute and University College London in the UK are developing LungVax, based on similar technology to the Oxford/AstraZeneca COVID-19 vaccine. The vaccine will target cells that carry lung cancer neoantigens, and if it makes it through clinical trials, could be used in people at risk of lung cancer, including current and ex-smokers. ^[17]

Allergies

Allergies affect a great many people worldwide, and range from inconvenient to life-threatening. Vaccines could be used to treat existing allergies in people. Examples of therapeutic candidates in development includes: 

● Angany's ANG-101 has entered a Phase I clinical trial for cat allergy ^[18]

● Desentum's DM-101PX has entered a Phase I clinical trial for birch pollen allergy; others in development include peanut and grass pollen allergies ^[19]

● The University of California is developing a peanut allergy vaccine ^[20]

● Shionogi and FunPep's FPP004X is in development for use at the beginning of the season to relieve pollen allergy symptoms [21]

Addiction

Vaccines against drugs of abuse have been considered since the 1970s, both as treatments and as prophylactics in certain groups. Clinical trials have been carried out with vaccines against nicotine, cocaine, methamphetamine and opioids, but there hasn't yet been evidence of efficacy. ^{[22, 23]}

Vaccines against addiction would come with ethical and social issues. Vaccination could be see as taking away people's autonomy, and could drive a market for alternative drugs of abuse. People who had been vaccinated may be regarded as high-risk individuals, affecting work and education prospects. ^[24]

Alzheimer's disease

Finding a treatment to slow or reverse Alzheimer's disease has been a major challenge. A vaccine approach has potential to be cheaper, safer and more effective than other treatments such as monoclonal antibodies. The first Alzheimer's disease vaccine, Elan Pharmaceuticals' AN-1792, entered clinical trials in 2002. It was designed to trigger antibodies against a form of amyloid-β known as Aβ42. Unfortunately, patients developed meningoencephalitis, an inflammation of the brain and its membrane as a result of the vaccine attacking healthy cells, and the trial was terminated. ^{[25, 26]}

While no Alzheimer's disease vaccine has yet reached the market, there are a number of vaccines in development aiming at different targets. Examples include: ^{[26, 27]}

● Amyloid beta oligomers

o Vaxxinity's UB-311, in Phase II

o AC Immune's ACI-24.060, in Phase II

o Alzinova's ALZ-101, in Phase Ib

o Nuravax's AV-1959D, in Phase I

o Nuravax's AV-1959R, in preclinical development

● Tau

o AC Immune's ACI-35.030, in Phase II

o Axon Neuroscience's AADvac1, in Phase II

o Vaxxinity's VXX-301, in preclinical development

o FunPep's vaccine, in preclinical development

o Nuravax's AV-1980R, in preclinical development

Parkinson's disease

There are no treatments yet that can stop, reverse or slow the progression of Parkinson's disease. The challenge in developing a vaccine as treatment is that the neurodegeneration can begin many years before diagnosis, and there aren't yet any biomarkers to be able to identify people at risk or at an early stage of the disease. Vaccines in development include: ^[28]

● AC Immune's ACI-7104.056, in Phase II

● Vaxxinity's UB-312, in Phase I

● Nuravax's PV-1950, in preclinical development

References

1. Pollard, A.J. and E.M. Bijker, A guide to vaccinology: from basic principles to new developments. Nat Rev Immunol, 2021. 21(2): p. 83-100.

2. Wolfe, N.D., C.P. Dunavan, and J. Diamon, A16: Origins of major human infectious diseases, in Improving Food Safety Through a One Health Approach: Workshop Summary. 2012, National Academies Press (US): Washington (DC).

3. Sadanand, S., Putting smallpox out to pasture. Nature Milestones: Vaccines, September 2020. Available from: https://www.nature.com/articles/d42859-020-00007-6.

4. Berche, P., Life and death of smallpox. Presse Med, 2022. 51(3): p. 104117.

5. Flemming, A., The origins of vaccination. Nature Milestones: Vaccines, November 2020. Available from: https://www.nature.com/articles/d42859-020-00006-7.

6. Staff writer. Cancer Treatment Vaccines. National Cancer Institute. 24 September 2019. Available from: https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/cancer-treatment-vaccines.

7. Incollingo, B.F., Sipuleucel-T Soon Available to Patients in Europe and Beyond. OncLive, 2014. Available from: https://www.onclive.com/view/sipuleucel-t-soon-available-to-patients-in-europe-and-beyond.

8. Fan, T., et al., Therapeutic cancer vaccines: advancements, challenges, and prospects. Signal Transduct Target Ther, 2023. 8(1): p. 450.

9. Philpott, J., 2023 in review: Cancer vaccines dose up on advances with tailored approaches Pharmaceutical Technology, 22 December 2023. Available from: https://www.pharmaceutical-technology.com/features/2023-in-review-cancer-vaccines-dose-up-on-advances-with-tailored-approaches/.

10. Weiser, P., Emerging Anti-Cancer mRNA Vaccines in the Pipeline. Managed Healthcare Executive, 22 December 2023. Available from: https://www.managedhealthcareexecutive.com/view/emerging-anti-cancer-mrna-vaccines-in-the-pipeline.

11. Bradford, S., Cancer Vaccination as a Promising New Treatment Against Tumors. The Scientist, 15 March 2024. Available from: https://www.the-scientist.com/cancer-vaccination-as-a-promising-new-treatment-against-tumors-71697.

12. Staff writer. FDA Approves Talimogene Laherparepvec to Treat Metastatic Melanoma. National Cancer Institute. 25 November 2015. Available from: https://www.cancer.gov/news-events/cancer-currents-blog/2015/t-vec-melanoma.

13. Frazer, I.H., The HPV Vaccine Story. ACS Pharmacol Transl Sci, 2019. 2(3): p. 210-212.

14. Stewart, J. Gardasil 9 FDA Approval History. Drugs.com. 7 September 2020. Available from: https://www.drugs.com/history/gardasil-9.html.

15. Merelli, A., HPV vaccine study finds zero cases of cervical cancer among women vaccinated before age 14. STAT, 25 January 2024. Available from: https://www.statnews.com/2024/01/25/hpv-vaccine-prevent-cervical-cancer-cervarix-gardasil-study/.

16. Palmer, T.J., et al., Invasive cervical cancer incidence following bivalent human papillomavirus vaccination: a population-based observational study of age at immunization, dose, and deprivation. J Natl Cancer Inst, 2024.

17. Staff writer, New funding for development of world's first lung cancer vaccine. University of Oxford. 22 March 2024. Available from: https://www.ox.ac.uk/news/2024-03-22-new-funding-development-worlds-first-lung-cancer-vaccine.

18. Philippe-Maisonneuve, N., Angany announces First-in-Human Clinical Study on ANG-101, a Vaccine Candidate to Treat Cat Allergy. Angany. 5 October 2023. Available from: https://angany.com/angany-announces-first-in-human-clinical-study-on-ang-101-a-vaccine-candidate-to-treat-cat-allergy/.

19. Mattila, P., Desentum raised 12 million euros for advancing allergy vaccine development. 8 February 2024. Available from: https://desentum.fi/news/desentum-raised-12-million-euros-for-advancing-allergy-vaccine-development-2/.

20. Staff writer, COVID-19 Vaccine Development Advances The Search For A Potential Peanut Allergy Cure. Allergen Bureau, 1 May 2023. Available from: https://allergenbureau.net/covid-19-vaccine-development-advances-the-search-for-a-peanut-allergy-cure/.

21. Staff writer, Announcement of Option Agreement between FunPep and SHIONOGI Regarding Allergy Vaccine Shionogi and FunPep. 4 March 2024. Available from: https://www.funpep.co.jp/en/wordpress/wp-content/uploads/2024/03/Announcement-of-Option-Agreement-between-FunPep-and-SHIONOGI-Regarding-Allergy-Vaccine.pdf.

22. Kinsey, B., Vaccines against drugs of abuse: where are we now? Ther Adv Vaccines, 2014. 2(4): p. 106-17.

23. Hossain, M.K., et al., Immunotherapies for the Treatment of Drug Addiction. Vaccines (Basel), 2022. 10(11).

24. Young, M.J., et al., Immune to addiction: the ethical dimensions of vaccines against substance abuse. Nat Immunol, 2012. 13(6): p. 521-4.

25. Schnabel, J., Vaccines: chasing the dream. Nature, 2011. 475(7355): p. S18-9.

26. Newton, W., Inside the hunt for an Alzheimer's disease vaccine. Clinical Trials Arena, 16 December 2022. Available from: https://www.clinicaltrialsarena.com/features/alzheimers-vaccine/.

27. Benisek, A., Is an Alzheimer's Disease Vaccine Possible? WebMD, 20 January 2024. Available from: https://www.webmd.com/alzheimers/alzheimers-disease-vaccine-possibility.

28. Shah-Neville, W., Is a vaccine for Parkinson's disease possible? Labiotech, 17 October 2023. Available from: https://www.labiotech.eu/in-depth/vaccine-parkinsons-disease/.

About the Author:

Suzanne Elvidge

Based in the north of England, Suzanne Elvidge is a freelance medical writer with a 30-year experience in journalism, feature writing, publishing, communications and PR. She has written features and news for a range of publications, including BioPharma Dive, Pharmaceutical Journal, Nature Biotechnology, Nature BioPharma Dealmakers, Nature InsideView and other Nature publications, to name just a few. She has also written in-depth reports and ebooks on a range of industry and disease topics for FirstWord, PharmaSources, and FierceMarkets. Suzanne became a freelancer in 2006, and she writes about pharmaceuticals, consumer healthcare and medicine, and the healthcare, pharmaceutical and biotechnology industries, for industry, science, healthcare professional and patient audiences.