### The Evolution and Future Outlook of Vaccine Development

By Taylor Smith

Vaccines have played a central role in the fight against contagious diseases among human populations for the past 200 years. For instance, global vaccination initiatives have helped to eradicate smallpox and polio in all but the most remote populations. Even yearly influenza vaccines have greatly reduced the number of mortalities each year from the common flu, and childhood vaccines have made a major impact in lowering childhood and adult morbidity resulting from infectious diseases.

However, there are certain diseases that have eluded scientists and researchers. Specifically, malaria and HIV/AIDS have posed continual challenges as these diseases ravage parts of the world where vaccines are needed most. Distribution is actually a significant roadblock in the effectiveness of vaccine development and use. Many of the globe’s poorest regions lack the infrastructure to inoculate their own populations. In addition, ethical and religious reasons pose potential deterrents, giving rise to the resurfacing of historic diseases that the majority of the world is protected from.

Finally, cost has been known to undermine efforts in vaccine development. According to the National Center for Biotechnology Information (NCBI), “the cost of developing a vaccine — from research and discovery to product registration — is estimated to be between $200 million and$500 million per vaccine. This figure includes vaccines that are abandoned during the development process.” (ncbi.nlm.nih.gov).

In combination with the cost of development, the timeline for safe and effective vaccine development typically takes 10 years on average (cdc.gov). The Centers for Disease Control and Prevention (CDC) outlines the general stages of vaccine development including the exploratory stage, pre-clinical stage, clinical development, regulatory review and approval, manufacturing, and quality control.

Clinical development is a three- to four-phase process. During the first phase, small groups of self-elected individuals receive the trial vaccine. In phase two, the clinical study is expanded and the vaccine is given to people who have characteristics (such as age and physical health) that are akin to those for whom the vaccine is intended. In the final phase, before FDA approval, the vaccine is administered to and tested upon thousands and checked for safety and effectiveness. Many vaccines undergo a fourth trial phase for additional review and testing.

French print in 1896 marking the centenary of Jenner’s vaccine.

A Brief History of Vaccines

The smallpox vaccine was the first known successful vaccine, introduced by Edward Jenner in 1796. An English country doctor from Gloucestershire, Jenner had observed that milkmaids who previously caught cowpox didn’t catch smallpox (the disease that had killed millions of people over the centuries). Symptoms included severe skin eruptions and dangerous fevers in humans, while cowpox, as it appeared in cows, resulted in blistering on the udders.

On May 14, 1796, Jenner removed fluid from a cowpox infected cow and scratched it into the skin of an 8-year-old boy. A single blister arose on the infected area, but no smallpox resulted in the child. It wasn’t long before doctors all over Europe began adopting Jenner’s vaccine technique. Jenner set such a precedent with his concept of inoculation that it continued to serve as a model for vaccine development in the 19th and 20th centuries. Diseases like whooping cough, polio, yellow fever, measles, typhoid, tetanus, and hepatitis B were eventually much less life-threatening to millions of people due to the availability of these vaccinations, which were typically administered during childhood.

With each passing decade, the recommended combination of infant and childhood vaccination schedules changed. For example, during the 1940s, physicians suggested that children receive smallpox, diptheria, tetanus, and pertussis (given in combination as DTP).

The polio inoculation in 1957 at the University of Pittsburgh, where Jonas Salk’s team had developed the vaccine.

The 1950s signaled the arrival of the polio vaccine, something that families around the world were diligently waiting and hoping for. Invented by Jonas Salk, it was licensed for approval in 1955. More vaccines followed in the 1960s such as measles, mumps and rubella (combined into the MMR vaccine in 1971). By the mid 1970s, smallpox was no longer on the recommended vaccination list since it had been essentially eradicated.

The vaccine for hepatitis B was approved in 1985 and was recommended by almost all pediatric physicians by 1989. The most recent vaccines include varicella for chickenpox (approved in 1996), rotavirus (1998-1999), hepatitis A (2000), and pneumococcal vaccine (2001). The oral polio vaccine was discontinued in 2000.

Adult vaccines have become more widely available, such as Shingrex, approved in 2017, which offers more protection from the shingles virus than its predecessor, Zostavax.

So, how do modern vaccines differ in origination from the first smallpox vaccine? Simply put, Jenner’s vaccine consisted of live, “attenuated” virus (meaning a weakening of the original virus to the point where it causes the development of antibodies rather than severe illness). Some vaccines will still provoke an immune response, such as feeling slightly ill after a tetanus or influenza shot. However, most people are completely unbothered and experience no side effects.

In contrast to live, attenuated viruses, some modern day vaccines use dead bacteria or parts of an inactive virus, which still provokes an immune response. Inactivated forms of toxins may also be employed to protect against future infection. In this way, the body “recognizes” the virus when they encounter exposure, but they are not significantly sickened by it.

The COVID-19 Crisis

In 2020, the global community is experiencing the COVID-19 pandemic and the rush to produce a vaccine that could potentially prevent “2-3 million deaths every year,” according to the World Health Organization’s (WHO) website (who.int).

WHO states, “There are currently more than 100 COVID-19 vaccine candidates under development, with a number of these in the human trial phase. WHO is working in collaboration with scientists, business, and global health organizations through the ACT Accelerator to speed up the pandemic response. When a safe and effective vaccine is found, COVAX (led by WHO, GAVI, and CEPI) will facilitate the equitable access and distribution of these vaccines to protect people in all countries. People most at risk will be prioritized.” (who.int/emergencies/diseases/novel-coronavirus-2019).

While the exact timeline of when and under what circumstances a COVID-19 vaccine will be issued and delivered remains unclear, physicians emphasize the importance of getting a vaccine that is already routinely available — the yearly flu shot. With fears of a new wave of COVID-related illness striking this winter, medical officials are advising that the flu shot is more important now than ever. Whether or not one is considered a “high risk” flu patient, the 2020 flu vaccine will help to protect people against the possibility of becoming sick with both COVID-19 and influenza.

Stephen M. Han, M.D., FDA commissioner, and Peter Marks M.D, Ph.D, director, Center for Biologics Evaluation and Research, publicly announced, “We are committed to expediting the development of COVID-19 vaccines, but not at the expense of sound science and decision making. We will not jeopardize the public’s trust in our science-based, independent review of these or any vaccines. There’s too much at stake.” (fda.gov).

A fourth phase three clinical trial began in September and it is expected that “up to 60,000 volunteers will be enrolled in the trial at up to nearly 215 clinical research sites in the United States and internationally.” (nih.gov/news-events). The investigational vaccine was developed by Janssen Pharmaceutical Companies of Johnson & Johnson.

According to nih.gov, “The Janssen vaccine candidate is a recombinant vector vaccine that uses a human adenovirus to express the SARS-CoV-2 spike protein in cells. Adenoviruses are a group of viruses that cause the common cold. However, the adenovirus vector used in the vaccine candidate has been modified so that it can no longer replicate in humans and cause disease. Janssen uses the same vector in the first dose of its prime-boost vaccine regimen against Ebola virus disease that was recently granted marketing authorization by the European Commission.”

In the background, some fears surround the safety of the COVID-19 vaccines and whether they would potentially be approved for emergency release to the public at the risk of the general population. As political pressure mounts around the race for the vaccine, few details have been released as to the cause of adverse reactions among two patients involved in an AstraZeneca trial. As of October 2020, all of the drug makers involved in clinical trials have signed a safety pledge promising to not cut corners when it comes to producing a vaccine that is both safe and effective for all populations.

The bottom line is that medical researchers across the globe are looking for a preventative tool to help control the spread of SARS-CoV-2 in the form of a safe and approved vaccination that can easily be distributed worldwide.

In the meantime, handwashing, social distancing, wearing masks, limiting travel, and disinfecting surfaces are the public’s main lines of defense against COVID-19.

While many experience signs and symptoms of COVID-19 differently, the CDC recommends that individuals should seek emergency medical attention in the case of trouble breathing, persistant pain and/or pressure in the chest area, new/unusual confusion, difficulty staying awake, and bluish lips or face. Call 911 or your local emergency medical facility to let them know that you are coming. In addition, rapid COVID-19 tests are increasingly available in most towns and cities throughout the country. Results are administered in 20-30 minutes.