Vaccines are among the 20th century’s most successful and cost-effective public health tools to prevent disease, disability and death. Not only do they prevent a vaccinated individual from developing a potentially serious disease, vaccines routinely recommended for children also help to protect entire communities by reducing the spread of infectious agents.

Immunizations have eradicated smallpox, eliminated poliomyelitis in the Americas, and controlled measles, rubella, tetanus, diphtheria and other infectious diseases. These are tremendous accomplishments; but, more remains to be done. Promoting optimal health through the administration of safe and effective vaccines will continue to be a priority for the biopharmaceutical industry.

For example, conventional vaccine approaches have not been as effective against rapidly evolving pathogens such as influenza or emerging disease threats such as the Ebola or Zika viruses. RNA-based vaccines could have an impact in these areas because of their shorter manufacturing times and greater effectiveness. Beyond infectious diseases, RNA vaccines also show potential as novel therapeutic options for major diseases such as cancer.

Testing

Q:What are the general stages involved the development cycle of a vaccine?

A:Broadly speaking the process can be broken down into the following stages

• Exploration and discovery
• Preclinical 
• Clinical development
• Regulatory review and approval
• Manufacturing
• Quality control

Q:In terms of coronavirus, when will have a vaccine?

A:Most likely, we already have one! Many pharmaceutical companies are working to develop a vaccine and, as reported in the media, some individuals have already been treated. Clinical trials are already underway to assess whether the candidate vaccines can effectively induce the recipient to produce antibodies against COVID-19. 

Q:When is a person considered to be vaccinated?

A:When the treated person develops antibodies against the antigen in the vaccine. A fuller explanation would be to say that if the treated person moves to a different location, subsequently comes into contact with an infected person and does not contract the disease. However, that is quite a time-consuming and not very scientific process, so the successful production of antibodies is generally agreed to be the de facto definition of being vaccinated.

Q:How does the process start?

A:Before we start with human testing, there will be a potential new drug, an idea or a novel therapeutic that could potentially be developed into a treatment. For example, there are a number of different types of vaccine. Scientists often use the virus itself, kill it or weaken it, and then expose people to the attenuated strain. Other types of vaccines only use specific fragments of the virus.

The non-clinical evaluation of vaccines includes the initial testing of candidate formulations in cell culture and animal models. Once these steps have been completed, we can move into humans.

Clinical development is a three-phase process. During Phase I, small groups of people receive the trial vaccine. In Phase II, the clinical study is expanded and vaccine is given to people who have characteristics (such as age and physical health) that similar to those for whom the new vaccine is intended. In Phase III, the vaccine is given to thousands of people and tested for efficacy and safety.

Q:So, if people have been treated and have been shown to produce antibodies, why can’t everyone be vaccinated?

A:Testing in humans occurs in various stages or phases. Initially, we have a new and untested pharmaceutical substance (the vaccine) and need to make sure that it works (efficacy) and, perhaps more importantly, is safe and has no adverse side-effects. This is done in clinical trials.

• A Phase I trial is done with healthy volunteers to assess the drug’s safety and tolerability. Participants are selected from the most robust section of the population before moving on to other more susceptible groups. From experience, these are normally healthy adult males (18–50 years old). Women are typically excluded because of potential pregnancy issues. Once these candidates develop antibodies without displaying any sever side-effects, then the trial can expand.
• A Phase II trial is done with a limited number of sick people and the key endpoint is efficacy. For vaccines, Phases I and II can sometimes be combined because the participants aren’t required to have a specific illness (such as diabetes). At this stage, older, younger and female volunteers can be included in the test population, as well as those who aren’t 100% healthy.
• A Phase III trial is a large-scale study with hundreds or thousands of people of all kinds of ages, conditions, etc. 

Throughout the trial process, records are kept regarding how each individual reacts to the treatment, what happens if someone already infected with the virus (in this case) is vaccinated and/or whether people from different racial/geographical backgrounds react differently. This is a complex and lengthy step-by-step process. You need to be sure that it works and it’s safe. Only when you are convinced that both objectives have been achieved in one stage can you move on to the next.

It’s critical to point out that everyone involved in a clinical trial is a volunteer, and enrolling (find, inform, assess them for medical compatibility) the number of people to validate the testing can be time-consuming.

Q:Who runs the trials?

A:A wide range of companies, academic institutes and organizations are currently running COVID-19 trials, both independently and in collaboration with partners: from small universities to global pharmaceutical giants (such as AstraZeneca and Pfizer), including agile, research-oriented bodies such as the University of Oxford, etc.

Approval

Q:What are the general stages involved the vaccine product approval process?

A:in the United States, the US Food and Drug Administration’s Center for Biologics Evaluation and Research (CBER) is responsible for regulating vaccines. The sponsor of a new vaccine product follows a multi-step approval process, which typically includes

• An Investigational New Drug application
• Prelicensure vaccine clinical trials
• A Biologics License Application (BLA)
• Inspection of the manufacturing facility
• Presentation of findings to FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC)
• Usability testing of product labeling

All the tests need to be reviewed by the authorities in the country where the product will be marketed and used: US FDA in America, EMA in Europe (for most countries) and other geographies may refer to the WHO if they don't have a local regulatory body. This, again, takes time. 

Someone must take responsibility, from a control point of view, that the data provided by the company who wants to produce/sell the vaccine is accurate, real and reliable. It must be cross-checked and validated, which all adds to the timeline. The US does offer a fast-track option, which, in emergency situations, can be applied implemented to reduce the overall timeframe (If the Phase II study results are positive, a large Phase III trial could be initiated and volunteers enrolled without a formal approval in place). 

Manufacturing

During the development of any vaccine and before mass production can begin, a large-scale (Phase III) clinical trial must be done. At the same time, full manufacturing capacity must be ensured and the production process must be optimized. Existing production facilities and capacities cannot simply be ramped up or expanded at will.

Q:How is the vaccine made?

A:To make enough vaccine to test a few hundred people, the process can be done in glass reactors on a benchtop. However, to make enough for several billion people, that’s a different story. This is a two-stage process. First, we need to make the active pharmaceutical ingredient (API) itself and, depending on the type of vaccine, this might be a few micrograms up to several milligrams per dose using a biotechnological fermentation process, followed by separation and purification. The challenge is to scale-up the procedure from the bench to industrial-sized manufacturing equipment.

Q:I’ve heard about an mRNA vaccine. What is it?

A:Unlike a conventional vaccine, RNA vaccines work by introducing an mRNA sequence (the molecule which tells cells what to build), which is coded for a disease-specific antigen. Once produced within the body, the antigen is recognized by the immune system, preparing it to fight the real thing.

RNA vaccines are highly specific, faster and cheaper to produce than traditional vaccines, and an RNA-based vaccine is also safer for the patient, as they are not produced using infectious elements. The production of RNA vaccines is laboratory based and the process can be standardized and scaled-up very quickly, allowing quick responses to large outbreaks and epidemics.

They’re very effective: needing only 50 µg per person, 50 mg of mRNA vaccine would enable you to treat 1000 people and 50 g would treat one million people. This means that you don’t need a huge manufacturing plant to make a lot of vaccine! As a comparison, 50 g is the total amount of alcohol in half a bottle of wine! On the flip side of the coin, however, there are no mRNA vaccines currently on the market.