Why Developing a COVID-19 Vaccine Is So Challenging

The race to find a safe and effective vaccine for COVID-19 (coronavirus disease 2019) is without precedent in modern medical history. Not since the AIDS pandemic if the 1980s and 90s have scientists, governments, and businesses come together in a coordinated effort to share knowledge and resources that may one day lead to the development of a fully protective vaccine.

As with the AIDS pandemic, there is much that scientists have to learn about the virus.

But there is hope. As of December 2020, there were no less than 233 vaccine candidates in active development in North America, Europe, and Asia, with the aim of bringing at least one fully to market by 2021.

On December 11 the Food and Drug Administration (FDA) granted emergency use authorization for a COVID‑19 vaccine candidate co-developed by Pfizer and BioNTech. This emergency use is approved for people ages 16 and older. Another COVID-19 vaccine candidate from Moderna was granted emergency use authorization on December 18. Both vaccines are novel messenger RNA (mRNA) vaccines that carry genetic instructions for our immune cells to make part of a protein that triggers an immune response to COVID-19.

Goals and Challenges

The timeline itself poses enormous challenges. Given that vaccines take an average of 10.71 years to develop from the start of preclinical research to the final regulatory approvals, scientists are tasked with compressing the timeline in a way that is largely unheard of in vaccine research.

In order for a vaccine to be considered viable, it needs to safe, inexpensive, stable, easily manufactured on a production scale, and easily administered to as many of the 7.8 billion people living on the planet as possible.

At the same time, if a vaccine is to end the pandemic, it will need to have a high level of efficacy, even higher than that of the flu vaccine. Anything short of this may temper the spread of infections, but not stop them.

Vaccine Efficacy

According to the World Health Organization (WHO), in order for a vaccine to completely eradicate COVID-19, it needs to be no less than 70% effective on a population basis and provide sustained protection for at least one year. At this level, the virus would be less able to mutate as it passes from person to person and more likely to generate herd immunity (in which large sectors of the population develop immune resistance to the virus).

These benchmarks are incredibly ambitious, but not impossible.

At 60% efficacy, the WHO contends that outbreaks would still occur and that herd immunity would not build aggressively enough to end the pandemic.

A COVID-19 vaccine with 50% efficacy, while beneficial to high-risk individuals, would neither prevent outbreaks nor reduce the stress on frontline healthcare systems should an outbreak occur.

The efficacy of the influenza vaccine, for example, was less than 45% during the 2019-2020 flu season, according to the Centers for Disease Control and Prevention (CDC). Some of the individual vaccine components were only 37% effective.

Health authorities may approve a vaccine with less-than-optimal efficacy if the benefits (particularly to the elderly and poor) outweigh the risks.

Cost

A vaccine cannot be considered viable if it is not affordable.

Unlike the flu vaccine, which is mass-produced by injecting chicken eggs with the virus, neither COVID-19 nor any of its coronavirus cousins (like SARS and MERS) can be reproduced in eggs. Therefore, a whole new production technology is needed to match the production volume of the annual flu vaccine, of which over 190 million doses are supplied in the U.S. each year.

New genetic vaccines, including the Pfizer-BioNTech and Moderna vaccine candidates, are developed in test tubes or tanks. They don't need to be grown in eggs or cells, which saves time and cost in development. Although, this is the first time they would be mass produced so full costs and many logistics are still unknown.

The U.S. has contracts to purchase doses of the mRNA vaccine candidates from Pfizer-BioNTech and Moderna, but the costs and accessibility of these vaccines and others in many countries throughout the world is still undetermined.

The U.S. government has a contract with Pfizer and BioNTech for an initial order of 100 million doses for $1.95 billion and the rights to acquire up to 500 million additional doses. Those who receive the vaccine get it for free. The vaccine has also received emergency use authorization in the UK, Bahrain, Saudi Arabia, Canada, and Mexico.

The federal government has $1.5 billion contract with Moderna for 100 million doses of the vaccine and the option to acquire an additional 400 million doses (It has already requested an additional 100 million). It also helped fund its development with a $955 million contract, bringing the initial total to $2.48 billion. If it receives emergency authorization, it will also be given to people in the U.S. for free.

Distribution

After COVID-19 vaccines are developed, the next challenge is distributing them fairly, particularly if production capacity is limited. This requires extensive epidemiologic research to determine which populations are at greatest risk of illness and death.

In order to sidestep these concerns, some experts recommended that funding be directed to tried-and-true vaccine models that are more likely to be scalable rather than experimental ones that may require billions of dollars in structural investment before the first allotment of vaccine is even produced.

Major investments were made on experimental ones, however, even if they pose challenges for mass distribution, including potential costs and ultra-cold temperature requirements for the Pfizer-BioNTech vaccine that need specialized freezers.

Ethical Dilemmas

Fast-tracking a vaccine minimizes some of the checks and balances designed to keep people safe. This doesn't mean that doing so is impossible. It simply demands greater oversight from regulatory watchdogs like the WHO, the National Institutes of Health (NIH), the European Medicines Agency (EMA), and the Chinese Food and Drug Administration (CFDA), among others, to ensure that research is conducted safely and ethically.

"Challenge studies," for example, involve the recruitment of previously uninfected, healthy, young adults who are directly exposed to COVID-19 after undergoing vaccination with the candidate vaccine. If a challenge vaccine proves safe and effective in this low-risk group, the next step would be to recruit higher-risk adults in a traditional double-blinded trial. While challenges like this are used with less deadly diseases, like flu, deliberately exposing people to COVID-19 is considerably riskier.

As COVID-19 research moves from preclinical studies to larger human trials, dilemmas like these will place pressures on regulators to decide which risks in this new frontier are "acceptable" and which are not.

Where to Start

Scientists aren't starting from scratch when developing their COVID-19 vaccine models (called platforms). There are not only effective vaccines based on related viruses but experimental ones that have demonstrated partial protection against coronaviruses like MERS and SARS.

COVID-19 belongs to a large group of viruses called RNA viruses that include Ebola, hepatitis C, HIV, influenza, measles, rabies, and a host of other infectious diseases. These are further broken down into:

• Group IV RNA viruses: These include coronaviruses, hepatitis viruses, flaviviruses (associated with yellow fever and West Nile fever), poliovirus, and rhinoviruses (one of several common cold viruses
• Coronaviridae: A family of Group IV RNA viruses that include four coronavirus strains linked to the common cold and three that cause severe respiratory illness (MERS, SARS, and COVID-19)

Insight from these viruses, however scant, can provide researchers with the evidence needed to build and test their platforms. Even if a platform fails, it can point researchers in the direction of more viable ones.

Models for Vaccine Development

The race to find an effective COVID-19 vaccine is coordinated in large part by the WHO and global partners like the recently formed Coalition for Epidemic Preparedness Innovations (CEPI). The role of these organizations is to oversee the research landscape so that resources can be directed to the most promising candidates.

CEPI outlined the various platforms available for COVID-19 to build on. Some are updated models based on the Salk and Sabin polio vaccines of the 1950s and 60s. Others are next-generation vaccines that rely on genetic engineering or novel delivery systems (called vectors) to target respiratory cells.

There are benefits and drawbacks to each of the proposed platforms. Some of the vaccine types are easily manufactured on a production scale but are more generalized in their response (and, therefore, less likely to reach the efficacy rates needed to end the pandemic). Other newer models may elicit a stronger response, but little is known about what the vaccine might cost or if it can be produced on a global scale.

Of the 10 vaccine platforms outlined by CEPI, five have never produced a viable vaccine in humans. Even so, some (like the DNA vaccine platform) have created effective vaccines for animals.

Vaccine Development Process

Even if the stages of vaccine development are compressed, the process by which COVID-19 vaccines are approved will remain more or less the same. The stages can be broken down as follows:

• Preclinical stage
• Clinical development
• Regulatory review and approval
• Manufacturing
• Quality control

The preclinical stage is the period during which researchers compile feasibility and safety data, along with evidence from previous studies, to submit to governmental regulators for testing approval. In the United States, the FDA oversees this process. Other countries or regions have their own regulatory bodies.

Clinical development is the stage during which actual research is conducted in humans. There are four phases:

• Phase I aims to find the best dose with the fewest side effects. The vaccine will be tested in a small group of fewer than 100 participants. About 70% of vaccines make it past this initial stage.
• Phase II expands testing to several hundred participants based on the dose considered safe. The breakdown of participants will match the general demographic of people at risk of COVID-19. Roughly a third a Phase II candidates will make it to Phase III.
• Phase III involves thousands of participants in multiple sites who are randomly selected to either get the real vaccine or a placebo. These studies are typically double-blinded so that neither researchers nor participants know which vaccine is administered. This is the stage where most vaccines fail.
• Phase IV takes place after the vaccine has been approved and continues for several years to evaluate the vaccine's real-world efficacy and safety. This phase is also known as "post-marketing surveillance."

Timing

As straightforward as the process is, there are several things beyond vaccine failure that can add months or years to the process. Among them is timing. Although a vaccine candidate should ideally be tested during an active outbreak, it can be difficult knowing where or when one might occur.

Even in hard-hit areas like New York City and Wuhan, China, where further outbreak seems imminent, public health officials can intervene to prevent disease with measures like requiring people to self-isolate again. This is important to keep people healthy, but can extend vaccine trials over an entire season or year.

Vaccine Candidates in the Pipeline

As of December 2020, 56 vaccine candidates are approved for clinical research, while over 165 are in the preclinical stages awaiting regulatory approval.

Of the platforms approved for testing, inactivated vaccines are among the most common. This includes protein subunits, which use antigens (components that best stimulate the immune system) instead of the entire virus, and whole-cell inactivated vaccines, some of which use "boosting" agents like aluminum to increase the antibody response.

RNA and DNA vaccines are also well represented, as are vectored vaccines that use deactivated cold viruses to carry vaccine agents directly to cells.

Additional platforms include virus-like particles, vectored vaccines combined with antigen-presenting cells, and a live attenuated vaccine that use a weakened, live form of COVID-19 to stimulate an immune response.

The information in this article is current as of the date listed, which means newer information may be available when you read this. For the most recent updates on COVID-19, visit our coronavirus news page.