Why Is COVID-19 Vaccine Taking Such a Long Time to Develop?

The question on top of everyone’s mind is: When will the novel coronavirus vaccine be ready? Because until then none of us can feel safe and we will need to continue to socially distance and watch over our shoulder. Just look at Hong Kong, which is going through a second wave of infection as residents are coming back from Europe and the US and bringing the virus with them. With up to 50% of the infected people showing no symptoms, the threat of the infection will always be present unless the whole planet is vaccinated.

The message we hear consistently from the experts is that it will take at least 12-18 months to develop the vaccine and that is if we are lucky. Normally vaccine development takes years, not months. One vaccine, for example – for rotavirus which causes severe diarrhea in infants – took 26 years to create, of which 16 years went to clinical trials, reports CNN.

The good news is that the COVID-19 vaccine is already here, at least some early preclinical candidates; see Info-Tech note SARS-Cov-2: Virus Pathology, Treatment, Strategies, and More for details. Two of the candidates – one in China, the other by Moderna Therapeutics called mRNA-1273 – has entered clinical trials. But, as we wrote in Will AI Create the Coronavirus Vaccine?, there are also huge regulatory and manufacturing challenges that will need to be overcome before it is available.

Clinical trials: red tape or necessary evil to save lives?

The objective of clinical trials is to ensure that the new treatment – be it a novel vaccine, drug, dietary supplement, or medical device – is safe and that it delivers the desired result, i.e. gets the job done (which is known as its efficacy).

Hence there are at least four phases of clinical trials (there is also Phase 0 which is optional). Each phase involves a progressively larger number of volunteers and constitutes a separate set of clinical trials that must be approved before proceeding to the next phase. (And that’s after initial trials in animals are completed.) All clinical trial phases include a placebo – they compare people who received and did not receive the treatment (those people receive a placebo).

In the US, clinical trials are overseen by the FDA, which approves and licenses new treatments and can terminate clinical trials at any point out of clinical safety concerns or for failure to establish efficacy.

The four stages of clinical trials are:

• Phase I, Assessing Safety: In this phase a small group of people – usually 20 to 80 – receive the trial vaccine to evaluate its safety, efficacy, doses, and side effects. The questions that need to be answered during this phase are: is the vaccine safe and does it generate the expected immune response? This phase usually takes one to two years to complete.
• Phase II, Establishing Efficacy: The vaccine is given to several hundred people who are similar in age and physical health to the segment of the population for whom the vaccine is intended. (For example, children, people over 50.) This phase determines the vaccine’s efficacy and correct dosage and further evaluates its safety. (Notice the different verbs: “evaluate” in Phase I vs. “determine” in Phase II.) This phase takes two or more years to complete.
• Phase III, Final Confirmation of Safety and Efficacy: The vaccine is given to several thousand people to confirm its efficacy and safety. The number of participants is calculated so that researchers can observe statistical differences between the experimental group (which was given the vaccine) and the control group (which was given a placebo). Some trials involve hundreds of thousands of people. For example, the rotavirus vaccine mentioned earlier involved 130,000 participants, because the pharmaceutical companies involved in the trials needed to determine that the two new vaccines did not cause a bowel obstruction like another, older, vaccine that did. Phase III of clinical trials usually takes three to four years to complete.
• Many vaccines also undergo Phase IV clinical trials, Ongoing Safety Studies During Medical Use, after they have been approved and licensed. This is done to determine the full effect of the vaccine. Is there something about it that we didn’t know or didn’t notice earlier – side effects that manifest themselves after a long period of time or that are rare and so they were not caught in previous phases?

Clinical trials are meant to save lives, and therefore, it is a lengthy and rigorous process.

In vaccine development, you typically want to follow the volunteers’ immune response for at least a year in each phase of the clinical trials.

Phase I clinical trial of mRNA-1273

Just to give you an idea of what is involved in Phase I clinical trials for the mRNA-1273 COVID-19 vaccine candidate developed by Moderna Therapeutics and which began human clinical trials in Seattle on March 16 (in parallel with animal trials) – the below is abridged from the NIH news release announcing the trial:

• Researchers study doses of 25 microgram (mcg), 100 mcg, or 250 mcg.
• Study participants will receive two doses of the vaccine about 28 days apart.
• There are 15 people in each dose cohort (so 45 total), ages 18 to 55 years old.
• They will be engaged initially for about six weeks.
• The first four participants will receive one injection with the low dose, and the next four participants will receive the 100-mcg dose.
• Investigators will review safety data before vaccinating the remaining participants in the 25-mcg and 100-mcg dose groups and before participants receive their second vaccinations.
• Another safety review will be done before participants are enrolled in the 250-mcg cohort.
• Participants will return to the clinic for follow-up visits between vaccinations and for additional visits during the year following the second shot.
• They will be monitored for common vaccination symptoms and any other medical issues.
• The clinical trial protocol team will meet regularly to review safety data, and a safety monitoring committee will also periodically review trial data and advise NIAID.
• Participants will also be asked to provide blood samples at specified time points, which investigators will test in the laboratory to detect and measure the immune response to the experimental vaccine.

National Institute of Allergy and Infectious Diseases (NIAID) is part of NIH. It conducts and supports various stages of the vaccine development process, from basic immunology research to clinical testing of candidate vaccines. NIAID is funding this clinical trial.

We may be able to expedite clinical trials for COVID-19 vaccine

We may be able to expedite clinical trials for the COVID-19 vaccine because this is a completely new type of vaccine. There are three main vaccine types:

• Whole pathogen vaccines like flu or MMR
• Sub-unit vaccines like shingles and pertussis
• Nucleic acid vaccines

All three types imitate an infection and work by causing the body to produce white-blood cells and antigens to defend itself. Whole pathogen vaccines use deactivated (killed) or weakened virus to trigger the immune response. Sub-unit vaccines use, like the name suggests, just a part of the germ. And nucleic acid vaccines use even smaller components, such as the genetic material of the virus – DNA or RNA – to stimulate the body’s protective response.

The mRNA-1273 vaccine candidate by Moderna Therapeutics is this latter type of vaccine. Because it uses the genetic material of the virus – which does not require the virus itself, the vaccine candidate was built from the genetic information provided by China – it seems safer than traditional methods (whole pathogen), and that is also, by the way, why the development process to create the vaccine candidate was extremely quick. It took only two days from the time Moderna received information from China for its team to finalize the sequence for mRNA-1273. (Another company, Inovio Pharmaceuticals, reportedly created a prototype of a vaccine in just three hours.)

After a vaccine candidate is created, is goes into clinical trials (assuming it is approved by NIAID), and here is the wrinkle: because RNA-based vaccines like mRNA-1273 are so new, we do not have existing testing protocols – they have never been approved for use in humans. Nor have they been tested outside of development labs. So the parameters for the clinical trials like the ones you saw above for Phase I of mRNA-1273 need to be created. (If you ever tried to create a new process, you know that this takes some time, careful evaluation of options, trades-off, risks, etc. and lots and lots of discussions and emails.)

But wait, since we are not dealing with a whole virus, can we perhaps expedite the clinical trials even if we need to create them more or less from scratch? The answer is: maybe.

Moderna has collaborated with NIAID for two years, working on a vaccine against MERS-CoV (which is another coronavirus). So there is an existing relationship and trust. In fact, Moderna’s CEO Stéphane Bancel said that with mRNA-1273 “NIH, CDC, FDA, and others are collaborating like nothing I have ever seen before”, including lots of emails flying in the middle of the night.

Another reason is promising data from animal clinical trial data for MERS-CoV vaccine. With two viruses belonging to the same family and the mRNA technology being general enough, that’s another reason why the vaccine candidate for SARS-CoV-2 has been created so quickly and why the company could start clinical trials in record time (details below).

And now the company is already filing paperwork to start Phase II of clinical trials. However…

Vaccine manufacturing

Assuming the vaccine is approved, the next step is manufacturing. And here we run into another set of hurdles.

But before we get there, we need to revisit clinical trials, because more happens in Phases I-III than what I listed earlier, as clinical trials and preparation for vaccine manufacturing are closely intertwined:

• In Phase I, the pharmaceutical company must also determine what components should be added to the vaccine to preserve and stabilize it so that is does not break down and whether chemicals known as adjuvants should be added as well to boost the immune response. Any preservatives, stabilizers, and adjuvants needed for the final vaccine must be used during the clinical trials.
• In Phase II, the company developing the vaccine must define the methods to manufacture it, how to package it, etc. The focus is on manufacturing consistency so that each production run comes out with the same results. Interestingly enough, “the manufacture of the vaccine must also be completed in the building that would be used to make the final product.”
• In Phase III, which is the final development stage before the pharmaceutical company is licensed, it must work out the final specifications for the facility where the vaccine will be made and the assays used (to monitor quality), as well as vaccine expiration date, storage requirements, etc.

After successful completion of Phase III, the pharmaceutical company typically needs another one to two years to review all data and complete all paperwork to request the license for the product and to prepare its launch. And the FDA, which visits the site often during the entire process, usually takes an additional ten months to review submitted data.

Perhaps these last steps – final paperwork and review by the FDA – could be expedited by all involved parties, but we may not be able to rush the process as much as we’d like, because unlike with, say the flu vaccine, we have no established manufacturing process that could be adopted for COVID-19.

However, as we have seen so far, where there is a will there is a way, and Moderna’s timeline is encouraging:

• The company received the genomics sequence from China on January 11.
• Just 25 days later, on February 7, it completed the first batch for clinical trials – meaning it figured out the basics of vaccine manufacturing.
• On February 21, Moderna filed what is known as IND (Investigational New Drug application).
• On February 24, the first batch was shipped to NIH.
• On March 2, the FDA gave the approval to start clinical study.

That is just 25 days to manufacture the vaccine candidate and 51 days from start to FDA approval for Phase I of clinical trails. In the world of vaccine development, speed like this is unprecedented.

It seems that Moderna is moving quickly with vaccine production and that it will be able to scale it fast because of the mRNA-based platform that it is using. “Whether [we] make mRNA for a flu vaccine or a rare liver disease—it’s the same. It’s the same rooms, same reactors, same people,” says Moderna’s CEO Stéphane Bancel. Moderna is currently scaling up its manufacturing capacity towards millions of doses per month.

It also sounds like is may be easier to produce large doses of a mRNA vaccine than traditional ones (using whole pathogenes). Experiments by a German biopharmaceutical company, CureVac, on the rabies vaccine showed that a strong immune response was achieved with just one microgram of mRNA. The company says that this means that one gram of the mRNA-based coronavirus vaccine could be enough to vaccinate one million people and that maybe hundreds of grams would be enough for us all.

Too much at stake

We are still dealing with a very new technology though – RNA-based vaccines – which has never been tested outside of the development labs. Even if we are not dealing with a whole virus as in traditional methods, we do need to proceed with caution. There is too much as stake otherwise. The twentieth century contains a few horrific examples of failures around vaccines:

• In 1942, a yellow fever vaccine contaminated with Hepatitis B was given to more than 100,000 US troops, reports The Guardian. Nearly 150 of them died.
• In 1955, in what is known as the “Cutter Incident,” the vaccine manufacturer Cutter Laboratories did not properly deactivate the virus in the polio vaccine. This resulted in “one of the worst pharmaceutical disasters in US history” with 40,000 cases of polio, 260 people paralyzed, and ten dead.

As a result of the Cutter Incident, the US government tightened monitoring and regulation of vaccine manufacturing. The FDA now regularly inspects and tests vaccine manufacturing facilities and requests pharmaceutical companies to conduct safety monitoring and report the results.

While these two cases are examples of manufacturing errors, the 1976 example below is a lesson in caution for a different reason.

In February 1976, a bout of flu broke out on an army base in New Jersey, and concerns started to circulate that it was similar to the 1918 influenza, which caused a pandemic that killed somewhere between 17 million and 50 million (maybe as high as 100 million). The US government reacted by starting a vaccination program for the entire country. Approximately 45 million people were vaccinated in ten weeks with what became known as the “swine flu vaccine.”

The program was abruptly stopped a few months later when no cases were detected outside of that military base and when it became apparent that the vaccine resulted in a high number of cases of Guillain-Barré syndrome. In people with this condition, a person’s immune system starts attacking its own nervous system, eventually leading to whole body paralysis. 53 people who had been vaccinated and developed Guillain-Barré syndrome died.

It seems that the 1976 rush to nation-wide vaccination was partly driven by political reasons, and that the government also ignored warnings from clinical trials about one of the manufacturers using a different flu strand (ibid).

Trust

There is another reason why we should exercise caution. Just nine months ago, in June 2019, BBC published an article that reported the results of the largest global study into attitudes around immunization. The title of the article is “Vaccines: Low trust in vaccination 'a global crisis'.” The study that was reported had been conducted by the Wellcome Trust, a research charity in the UK, which surveyed 140,000 people in 140 countries.

The main finding? There are many people who don’t trust vaccination programs, and the differences are aligned geographically and they correlate with the level of prosperity: “people living in several higher-income regions were among the least certain about vaccine safety.” Read: they don’t believe that vaccines work or that they are safe. Meanwhile, we see resurgence of deadly diseases like measles that are entirely preventable.

The Wellcome Trust study did not explore the reasons for public mistrust, but there are multiple factors: complacency, vaccine side effects, and fears that scaling up manufacturing too fast may jeopardize vaccine safety (as was a concern in France at one time).

Then there are people who are concerned about a possible link between vaccines and other conditions, such as the one between MMR and autism. And your author recently came across a theory postulating that viruses like SARS-CoV-2 are “excretions of a toxic cell; they happen when the cell is poisoned” (by electro-magnetic radiation), and that the current pandemic is caused by 5G. Even for an open-minded analyst like me, this theory is a bit hard to comprehend.

Furthermore, for vaccines, like for many other things in life, the same maxim holds: Trust isn’t something that can be given out piecemeal; you either have it or you don’t. And once trust is damaged, it is very hard to restore it. If we were to rush through the clinical trials with COVID-19 and a tragedy happened similar to the 1955 Cutter Incident or the 1976 vaccination fiasco, some people may refuse vaccination even when the vaccine is safe. And we cannot afford silent carriers.

More to consider, such as continued funding, for example

There are many other things to consider:

Who will foot the bill? Since there are no vaccines on the market for any coronavirus, we are starting with a blank slate. That is expensive. Clinical trials and manufacturing at scale cost billions of dollars. In fact, Wellcome Trust put that number for coronavirus vaccine at $3 billion – that’s how much more money it will take to fund and produce the vaccine on top of what has already been spent.

The vaccine development effort so far has been led by the Coalition for Epidemic Preparedness Innovations (CEPI), a non-profit set up to coordinate R&D for vaccines against emerging infectious diseases. CEPI has invested nearly $30 million in vaccine development at Moderna, Inovio, and six other groups. (And in the US, NIAID is funding the first phase of clinical trials.)

CEPI also makes it possible for pharmaceutical companies to start developing manufacturing facilities while the vaccine is still in clinical trials. By doing this in parallel they hope to compress the overall timelines, even if this strategy is risky (the vaccine may not gain approval after all). But CEPI is running out of money. Can governments help? Private philanthropists? Big corporations? Money and resources seem to be flowing in; as an acquaintance of mine said, this is a great field to be in right now, but greater collaboration and more resources (read: funding) are needed.

And vaccine distribution and ethics

Assuming that we can manufacture the vaccine and do that at scale, the next question is distribution and ethics.

Vaccines must be licensed by the regulatory bodies in the countries where they are distributed. Licensing and approval require inspections of manufacturing facilities. Even procurement of vaccines by the UN agencies requires that the product has been pre-qualified by the WHO. Then the methods of distribution vary between countries and depend on national vaccination policies.

In the US and Canada one can obtain some vaccines from a family physician who orders them directly from a manufacturer or distributer. The flu vaccine is available in drugstores as OTC, though administered by medical professionals. In the EU, there is a wide range of distribution policies and buying models, and I’m just scratching the surface of a very complex picture of global of vaccine distribution and supply.

And since we can’t make the needed vaccine quantity all at once, even if small amounts seem to be needed as noted earlier – vaccine manufacturing will be scaled up over time, and in the meantime we will need to address questions such as these:

• Who should get it first?
• In which sequence will people be vaccinated?
• Which criteria will be used to determine that?
• And who will come up with them?
• Should we start vaccinating people even before the final approvals, on compassionate grounds or to protect medical staff?
• How much will the vaccine cost? And who will cover it for people who may not be able to afford it, especially among the underprivileged and in developing countries?

Who is going to address all of these ethical issues? Countries have closed borders against their neighbors and are folding onto themselves; people are hoarding masks and other personal protective equipment. And these questions need to be resolved at the global level for vaccination to be successful. (We hope to explore further this topic of ethics in a future note.)

Our Take

The overall news around COVID-19 vaccine development are encouraging. Two pre-clinical candidates (one described here and one in China) have entered clinical trials. (And up to 50 more are in the various stages of development.) And regulatory bodies are keen to expedite the process to make the vaccine(s) available as soon as feasible.

But many issues remain to be addressed, not least around further funding and global vaccine distribution including ethics. The world has come together in a remarkable display of solidarity and collaboration to create the vaccine to prevent further spread of COVID-19 (and to find other treatments and intervention strategies; see our note Data and Analytics in the Time of Pandemic for details). We need to continue working together; all of our lives are at stake. That includes staying at home as much as possible and keeping your distance when you do go out.