Blog: Health Matters

By Heather Davis, PhD and the Target Program Team

NOTE: SARS-COV-2 is the virus and COVID-19 is the disease caused by it.

With the appearance of a completely new virus that can infect and spread between humans, such as SARS-COV-2, no one will have any pre-existing immunity to fight the virus if they are exposed. The lack of protective immunity within the population (herd immunity) results in a higher rate of spread and greater severity of COVID-19 disease. The natural acquisition of herd immunity, as has been suggested by some, is not realistic. Everyone knows of the incredible strain on the medical system and the many deaths in Wuhan, China, and despite that, only about 1% of the Wuhan population was ever infected. That is not nearly enough to provide herd immunity, since, depending on the disease, 75-95% of the population must be protected to provide herd immunity to those who aren’t.

The greatest hope for dealing with the COVID-19 pandemic is to have a vaccine that can protect people from getting infected upon future exposure. Until we have a vaccine, the best way to control viral spread is social distancing to prevent people from being exposed to the virus at all. While shown to be effective, and thus being implemented in many countries, social distancing measures are extremely disruptive to society and the economy. We have been told it will be at least a year to develop a vaccine for SARS-COV-2. So why is it going to take so long?

Fact 1: First, what is a vaccine?  

• A vaccine is a type of medicine that “instructs” your immune system to develop responses that will recognize a specific pathogen (typically a bacteria or virus) or cell (cancer cell).
• Most vaccines are administered to healthy people to protect them from disease they might be exposed to in the future – these are called prophylactic vaccines. More recently, efforts have been made to develop vaccines that will treat a chronic disease, such as cancer – these are call therapeutic vaccines. For COVID-19, efforts are underway to develop a prophylactic vaccine.
• Vaccines contain antigens, which are specific to the pathogen being protected against, and adjuvants, that non-specifically enhance the immune responses against the antigen.
• The antigen is a component that looks just like (part of) the real pathogen, so that the response induced by the vaccine will be able to recognize and act against the pathogen if the person is ever exposed to it later in life. There are various ways vaccines can be made. One method used is to have the vaccine contain the whole virus that has been killed or attenuated so that it doesn’t cause disease, while another is to use a single viral protein or part of a protein, which is usually made synthetically (i.e., no virus is ever grown).
• Adjuvants are substances added to some vaccines that make the specific immune response to the antigen stronger. The most common adjuvant added to vaccines commonly used today is a small amount of aluminum hydroxide or aluminum phosphate (alum).  
• Vaccines can be administered by different routes, but the vast majority are injected into a muscle – typically the upper arm of adults and older children and the thigh of infants and toddlers. However, some vaccines are taken by mouth, sprayed into the nose or injected into the skin. Each vaccine must be used by the route indicated for it.
• Some vaccines can work with a single dose that provides lifelong protection. Other vaccines, especially the more purified ones, may require two or three doses to establish a good response, then another dose every five to 10 years to maintain good protection. All of this is worked out empirically through clinical testing, as there are no rules that apply to all.

• Several different approaches are currently being pursued towards developing a vaccine against COVID-19.

Fact 2: How is a new vaccine developed?

• The first step is to sequence the virus so that potential antigens can be identified – this has been completed for SARS-COV-2.
• Next, it is necessary to select what part of the virus the vaccine will target. Sometimes it is important to have immunity against multiple proteins in the virus; other times one is enough. This needs to be worked out for every disease.
• Then the method of making the vaccine is selected. This determines the types of immune responses induced as well as the duration of protection. The two main types of immune responses are antibodies and T cells. 
  • Antibodies recognize and bind to viruses in the blood stream, which prevents the virus from infecting new cells. 
  • T cells kill cells that are already infected. Not all types of vaccines induce T cells, so if T cells are required, development may be more complicated.
• Some types of vaccines are first tested in cell culture to identify that they are working as required and to select the best candidate(s) out of many.
• The best candidates are then tested in animals, typically mice, to select one that induces the best immune responses, and also to get an idea of what dose might be required for a human (often a human dose is only 10x a mouse dose, despite the very large difference in body size). These studies take weeks or months, since doses must be spaced weeks apart and it takes a few weeks for immune responses to develop after each dose. If there is an animal model for the disease, the vaccine can be tested for preventing the disease in animals. Unfortunately, for many diseases an animal model is not possible, and at present none exists for COVID-19. 
• A single candidate is selected based on animal data and then tested at high doses in animals for determining safety. This takes several months, in part because it must be done under strict legal requirements known as “good laboratory practice.” 
• While animal studies are underway, a different group of scientists work out the best way to manufacture large amounts of the vaccine consistently. They also develop and validate all the assays that will be used to ensure every lot of the vaccine is effective.
• At this point the vaccine is ready to be tested in humans, but first permission must be obtained from government regulators such as the FDA in the USA or the EMA in Europe. The review period is typically 30 days.
• The first clinical study, Phase 1, is in a small number of people to explore safety and dose response. Lower doses are tested before higher doses to ensure safety. Multiple administrations may be given, in which case they may be spaced a month or more apart. Then blood samples are taken and tested for immune responses. A Phase 1 trial often takes a year from beginning to end, including the setup time at the start and data analysis at the end.
• Next comes a Phase 2 trial, which tests one or two selected dose levels in a larger group of people to confirm that the vaccine works as expected (right type and amount of immune responses) and is safe.  Such trials typically take a year or more.
• The final Phase 3 trial needs to prove that the vaccine protects against the disease and is still safe in an even larger number of people. In cases where it is known exactly how much antibody response is required to protect a person from the disease, these trials only need to do blood tests. However, for a completely new disease like COVID-19, it is necessary to test the vaccine in the context of an ongoing epidemic or pandemic, with some trial participants getting the new vaccine and some getting placebo (the injected equivalent of a sugar pill), and efficacy is determined by seeing how many get infected in each group. Phase 3 trials can take up to several years, depending on what will be required to prove the vaccine is safe and efficacious.
  • An example of how a new vaccine against SARS-COV-2 could be tested in Phase 3 is to vaccinate health care workers who are dealing with COVID-19-infected patients and compare their infection rates to workers who use the same personal protection (masks, gloves, hazard suits) but get a placebo vaccine. Another approach would be to vaccinate family members of those infected or communities with very high infection rates.
  • In situations where the need is urgent, the regulatory bodies can choose to conditionally approve the vaccine based only on Phase 2 data, with Phase 3 confirmatory studies done after the vaccine is available for general sale. This will likely be the case for COVID-19.
• After the Phase 3 trial is complete (or Phase 2 if early conditional approval is being sought), the vaccine company prepares a dossier with all relevant data and submits it to the regulatory health bodies (FDA, EMA) to seek permission to be able to sell it. These dossiers can take up to six months to put together; then once the dossier is submitted, the authorities typically take one year to review before they provide licensure to sell the vaccine for use in the general population.

Fact 3: What are the challenges for developing a COVID-19 vaccine? 

• This is a brand new virus, so it is unknown what are the best antigen(s) to use and what type of immune responses will be required for protection.
• There is no animal model of the COVID-19 disease to test whether a potential vaccine is efficacious before administering it to humans.
• The Phase 3 trial will need to be done within the actual ongoing pandemic, since it is not known what level or types of antibodies will be protective.
• Several of the candidate vaccines are using new technologies not used in any existing vaccines. This means they may take longer to develop, and the risk of failure is greater.

Fact 4: When can we realistically expect a COVID-19 vaccine?

• As you can see from the information provided under Fact 2, it normally takes many years to develop a new vaccine – 10 years is not uncommon.
• Due to the exceptional and serious circumstances of the COVID-19 pandemic, efforts will be made to develop a vaccine as fast as possible. A time frame of 12-18 months has been mentioned, but this is unprecedented and will require both luck in getting the vaccine design/platform worked out quickly, as well as health regulators agreeing to faster review times and conditional approval based on Phase 2 data.

Fact 5: Are vaccines safe? 

• Yes. This shouldn’t be a question that even needs to be asked, but there is so much misinformation out there that I will address this as my last point.
• The vast majority of vaccines cannot under any circumstance cause the disease they are designed to protect against. Live attenuated vaccines carry some risk of causing problems in people who are immune suppressed, so certain vaccines (e.g., measles, oral polio) are not recommended for those who are immune compromised due to a genetic condition or treatment with immune suppressive drugs, such as anti-rejection drugs after organ transplant. It is because of these people, as well as newborns whose immune systems are not yet fully developed, that it is so important that everyone else be vaccinated, so that herd immunity can protect the vulnerable.
• There has been a lot of noise about vaccines causing autism. The whole story started with a disgraced UK medical doctor, Andrew Wakefield, who fabricated data saying that the measles, mumps & rubella (MMR) vaccine was responsible for causing autism in children. This was published in 1998 in a prestigious journal, The Lancet, but later retracted. Wakefield was ultimately found guilty of fraud and lost his medical license. The allegation that MMR vaccine causes autism is the most damaging medical hoax of the last century, and Wakefield can be credited with thousands of dead or disabled babies and children because his hoax convinced parents to not vaccinate against these three terrible diseases, which are 100% vaccine preventable.
• After the MMR controversy died down, vaccine critics then suggested that thimerosal, a mercury-containing preservative used in multi-dose vials of some vaccines, was the cause of autism (thimerosal was never in MMR vaccines). One of these was Dennis K. Flaherty, who published a damaging paper in 2011. Note that the form of mercury in vaccines is different than that found in fish, so any toxicity studies from eating too much mercury-containing fish are not necessarily relevant, and in any event, the doses in vaccines are extremely low. Many studies have been done that unequivocally proved no link between thimerosal and autism, but the anti-vaxxer movement was not swayed. Finally, to stop the noise, the government asked vaccine companies to make all pediatric vaccines in a single dose format, which is more expensive to make but doesn’t require thimerosal. It has been well over a decade since all childhood vaccines in the USA and Europe were mercury-free, yet the rates of autism have continued to climb.  

Until the world is offered protection from the SARS-CoV-2 virus by a new vaccine, we must take seriously the threat of infection and follow social distancing and other practices recommended by the WHO and our local authorities.

Sources:

• Wakefield AJ, Murch SH, Anthony A, Linnell J, Casson DM, Malik M, et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. The Lancet. 1998; 351:637–41.
• Hurley AM, Tadrous M and Miller ES. Thimerosal-containing vaccines and autism: a review of recent epidemiological studies. Journal of Pediatric Pharmacology and Therapeutics 2010; 15:173-181.
• Flaherty et al., Annals of Pharmacotherapy 2011; 45:1302-04.