Patricio V Marquez and Betty Hanan

 

Typically, the development of new vaccines requires years of research and testing before being deployed.  In the case of the new COVID-19 vaccines, scientists have been racing to produce a safe and effective vaccine in record time.  In a historical feat, the trials of some of the vaccines have taken less than a year.   

As of today, researchers are testing 54 vaccines in clinical trials on humans, and at least 87 preclinical vaccines are under active investigation in animals.

In contrast, history shows that in some cases it took decades of work to develop vaccines.  For example, the eradication of smallpox through a vaccine--one of the biggest achievements in public health history —took several centuries.  After a decade of work, Max Theiler, developed the first safe and effective yellow fever vaccine in 1937, for which he receive the Nobel Prize in Physiology or Medicine in 1951.  Similarly, it took years of research to understand the complexities of the influenza virus, before the first vaccine was approved for use in the United States in 1945. And then, two years later in 1947, researchers concluded that seasonal changes in the composition of the virus rendered existing vaccines ineffective--there are two main types of influenza viruses that cause epidemic seasonal infections nearly every year, influenza A and influenza B, along with multiple new strains of the virus.  Because of this, scientists have had to adjust the influenza vaccine every year.

In this blog, we provide a snapshot of the development of some leading COVID-19 vaccines based on a quick review of available literature.

The Frontrunner COVID-19 Vaccine Candidates

1. Genetic Vaccines

Pfizer/BioNTech and Moderna have developed new COVID-19 vaccines using a new technology that has never before been approved for human use.  Both use a synthetic version of coronavirus genetic material, called mRNA, to program a person’s cells to churn out many copies of a fragment of the virus. That fragment sets off alarms in the immune system and stimulates it to attack as if the person were exposed to the real virus.  The two companies are the first to announce interim data from large studies.

Pfizer/BioNTech Vaccine

The companies announced on November 18, 2020 that the vaccine was safe.  Its 95% efficacy was consistent across age, race, and ethnicity, and it worked well in older people to prevent severe COVID-19 disease, well above the 50% efficacy level that the U.S. Food and Drug Administration (FDA) had said it would accept in order to grant emergency approval for vaccines. The most common serious adverse event was fatigue, with 3.7% of volunteers reporting tiredness after they took the second dose. Two percent of volunteers reported a headache after the second dose.

Pfizer submitted trial data and a request for emergency authorization for its COVID-19 vaccine to the FDA on November 20, 2020, with the expectation that a decision by the FDA for the vaccine’s use will be made by mid-December 2020.

The application will be reviewed by teams of the FDA’s Center for Biologics Evaluation and Research.   Key moments in the process are: the first comes two days before members of the FDA Advisory Committee meet, when the FDA typically releases its staff report on the clinical trial data, offering an insight into whether the agency is leaning toward authorizing the vaccine; and the second is at the end of the Committee process scheduled for December 10, 2020, when the Committee will take a non-binding vote on whether the FDA should clear the vaccine for public use.

Pfizer has also begun regulatory submissions in Australia, Canada, the European Union, Japan and the United Kingdom (UK). It has announced also that it plans to apply in other countries as well.

Moderna Vaccine

Positive interim results from a final-stage trial have been released. The next step will be submission to the FDA of a request for emergency authorization. This would follow shortly after the review of Pfizer’s vaccine.  The Moderna vaccine uses similar technology to the one from Pfizer and BioNTech. It is reported to have a 94.5% efficacy, and appears to prevent the COVID-19 disease, including severe cases. A big unknown, however, is how long the immunity provided by the vaccine will last.

Emergency Authorization Process

Both of the companies’ vaccine candidates began large human trials on July 27, 2020. Emergency authorization allows drugs and vaccines targeting COVID-19 to reach limited groups of people in the United States (US) much faster than through standard approval channels. The FDA review process normally takes about six to ten months, depending on the candidate’s priority status. 

Pfizer has indicated that if the FDA authorizes the two-dose vaccine, up to 50 million doses could be available by the end of the 2020, and up to 1.3 billion by the end of 2021.  It  is estimated that once the Pfizer/ BioNTech and the Moderna vaccines are authorized for emergency use, there will be enough doses to immunize about 20 million people in the United States before the end of 2020, a group that would most likely include health care workers and nursing home residents (there are an estimated 17 million to 20 million health care workers in the United States, and about a million people living in nursing homes).  The 50 million doses would also allow older people with co-morbid conditions to be immunized.

Pfizer/BioNTech and Moderna have arranged deals with the U.S. Government so that the vaccines will be free to the population and distributed according to plans worked out between the federal government and the states.

Cold Chain Requirements

After the FDA authorizes the use of the Pfizer/BioNTech and Moderna vaccines, the critical next step is vaccine deployment. The Pfizer/BioNTech vaccine must be stored at minus 94 degrees Fahrenheit, colder than any other vaccine in development. Pfizer will ship the vaccine in special boxes of 1,000 to 5,000 doses that are stuffed with dry ice and equipped with GPS-enabled sensors.  The vaccine can be stored in conventional freezers for up to five days, or in the special coolers for up to 15 days, as long as the dry ice is replenished and the boxes are not opened more than twice a day.  The Moderna vaccine must also be stored in a freezer long-term, but at minus 4 degrees Fahrenheit. The company has indicated that its vaccine could be stored at standard refrigerator temperatures of 36 to 46 degrees Fahrenheit for up to 30 days, which could make it easier to store than the Pfizer vaccine.

2. Viral Vector Vaccines

These vaccines contain viruses engineered to carry coronavirus genes. Some viral vector vaccines enter cells and cause them to make viral proteins. Other viral vectors slowly replicate, carrying coronavirus proteins on their surface.  And the viral proteins stimulate the body's production of antibodies to confer immunity.

AstraZeneca Vaccine

The British-Swedish company AstraZeneca and the University of Oxford have developed a vaccine based on a chimpanzee adenovirus (these are common viruses that cause a range of illness, such as cold-like symptoms, fever, sore throat, bronchitis, pneumonia, diarrhea, and conjunctivitis). 

In a press release on November 23, 2020, the company reported interim findings from two of their ongoing trials — one in the UK and one in Brazil. The trials used different approaches to inoculating the more than 11,000 people who participated, and found two levels of efficacy, which they averaged to 70 percent. The researchers also found no severe cases or hospitalizations in the study participants who got the vaccine.

According to the press reports, AstraZeneca, has pledged it will not make a profit on the vaccine during the pandemic.  It has reached agreements with governments and international health organizations that its cost will be $3 to $4 a dose.  In contrast, Pfizer’s vaccine is likely to cost about $20, while Moderna’s is $15 to $25, based on agreements the companies have struck to supply their vaccines to the U.S. Government.

The preliminary analysis also indicates that the vaccine did not just reduce cases of COVID-19 with symptoms, it also reduced the number of asymptomatic cases. This latter finding may mean that the vaccine will be good at reducing the transmission of the virus from person to person.  Another advantage of the vaccine is that it can be kept in a refrigerator for up to six months, unlike Pfizer and Moderna’s vaccines, which have to be frozen.

AstraZeneca has secured a series of agreements to provide vaccines to governments should they prove effective, including 300 million doses to the United States and 400 million doses to the European Union.  The company has noted that its total annual manufacturing capacity for the vaccine stands at three billion doses.   

However, since unveiling the preliminary results and after the original version of this blog was posted, AstraZeneca acknowledged on November 25, 2020, a key mistake in the vaccine dosage received by some study participants, adding to questions about whether the vaccine’s apparently spectacular efficacy will hold up under additional testing.  Scientists and industry experts said the error and a series of other irregularities and omissions in the way AstraZeneca initially disclosed the data have eroded their confidence in the reliability of the results.  Officials in the United States have noted that the results were not clear. The head of the flagship federal vaccine initiative suggested that the vaccine’s most promising results may not have reflected data from older people.

China’s CanSino Biologics Vaccine

The Chinese company CanSino Biologics has developed a vaccine based on an adenovirus called Ad5, in partnership with the Institute of Biology at the country’s Academy of Military Medical Sciences. After publishing promising results from a Phase 1 safety trial, and reports that Phase 2 trials that demonstrated the vaccine produced a strong immune response, the Chinese military approved the vaccine on June 25, 2020 for a year as a “specially needed drug”, but it is not clear whether vaccination would be mandatory or optional for soldiers.  Starting in August 2020, CanSino began running Phase 3 trials in a number of countries, including Saudi Arabia, Pakistan, and Russia.

Russia’s Sputnik V Vaccine

The Gamaleya Research Institute, part of Russia’s Ministry of Health, launched clinical trials in June 2020 of a COVID-19 vaccine. It is a combination of two adenoviruses, Ad5 and Ad26, both engineered with a coronavirus gene.  On August 11, 2020, President Vladimir V. Putin announced that a Russian health care regulator had approved the vaccine, named Sputnik V, before Phase 3 trials had even begun. However, it was later indicated that the approval was a “conditional registration certificate,” which would depend on positive results from the Phase 3 trials. Those trials, initially planned for just 2,000 volunteers, were expanded to 40,000. In addition to Russia, volunteers were recruited in Belarus, the United Arab Emirates, and Venezuela. On October 17, 2020, a phase 2/3 trial was launched in India.  On September 4, 2020, Gamaleya researchers published the results of phase 1/2 trials. In a small study, they found that Sputnik-V yielded antibodies to the coronavirus and mild side effects.  On November 11, 2020, the Russian Direct Investment Fund announced preliminary evidence from the Phase 3 trial indicating that the vaccine has a 92% efficacy. 

Russia has negotiated agreements to supply the vaccine to several countries including Argentina, Brazil, Mexico, and India.

China’s Sinovac Biotech Vaccine

Sinovac Biotech’s CoronaVac is in Phase 3 of clinical trials.  It uses inactivated virus, which can help the body develop antibodies to the pathogen without risking infection. The shot had already been approved in China for emergency use for doctors, customs officials, and other frontline workers, while simultaneously in Phase 3 trials in multiple other countries. 

How do Pharmaceutical Companies Determine the Efficacy of a Vaccine?

Clinical trials provide data and information about how well a vaccine prevents an infectious disease and about how safe it is. The fundamental logic behind today’s vaccine trials was worked out by statisticians over a century ago.  Researchers vaccinate some people and give a placebo to others, and then wait for participants to get sick and look at how many illnesses occur in each group.  From these numbers, researchers calculate the proportion of volunteers in each group who get sick. They determine the relative difference between those two fractions and express that difference with a value they call efficacy. If there is no difference between the vaccine and placebo groups, the efficacy is zero. If none of the sick people had been vaccinated, the efficacy is 100%.

A 95 percent efficacy is compelling evidence that a vaccine works well, but it does not tell what the chances are of a person becoming sick after being vaccinated. Also, it does not say how well the vaccine will reduce COVID-19 across a country.

Difference Between Efficacy and Effectiveness

Efficacy and effectiveness are related to each other, but they are not the same thing. Both terms refer to the ability to produce a desired or intended result, with a difference.  While efficacy refers to a result acquired under ideal or controlled conditions (e.g., in a clinical trial where the patient population and other variable factors can be controlled), effectiveness refers to how well a drug or vaccine works out in real-world situations, where the patient population and other variables cannot be controlled (e.g., differences in the underlying medical conditions of people vaccinated in the real-world compared to those in the clinical trials, how a vaccine is transported and stored, or even how patients are vaccinated). 

It is therefore possible that the effectiveness of coronavirus vaccines will or will not match their impressive efficacy in clinical trials. But if previous vaccines are any guide, effectiveness may prove somewhat lower.

The Importance of Pharmacovigilance

Post-vaccine surveillance needs serious attention given the risk of possible adverse vaccine effects.  Clinically important, adverse events following any vaccination must be reported by healthcare providers to the Pharmacovigilance System (PVS) as required of all vaccination providers. Adverse events can also be monitored through electronic health record and claims-based systems. 

This is important because before a vaccine is marketed, its safety and efficacy exposure are limited to its use in clinical trials.  Generally, clinical trials cover a limited number of patients with strict inclusion criteria, often excluding special patient groups like those with co-morbid conditions, children, elderly, and pregnant women.  Hence, they do not reflect the experience in larger populations and in different geographical regions.  People from different geographical regions differ from one another with respect to genetics, nutritional habits, lifestyle, and clinical practices.  This makes it obligatory to maintain a constant vigilance on the use of new vaccines during the post-marketing period.

Strong testing systems are essential for vaccine surveillance. Testing is a critical tool to be used alongside vaccines, given that: (i) vaccine-induced immunity must be monitored with testing at a population level; (ii) the real-world effectiveness of COVID-19 vaccines will be largely uncertain and possibly variable across settings and populations; and (iii) vaccine coverage will be incomplete and focused on priority populations.

It is also of paramount importance to get a baseline sero-surveillance study done - representative samples of target populations to receive the COVID-19 vaccine to be able to distinguish between infection and vaccine-acquired immunity.

Moving Forward

Vaccines not only protect the people who get them, but also, they can help drive down new infection rates and protect society as a whole by slowing the spread of the virus. However, as observed in an editorial at The Lancet, it should be clear that whether the COVID-19 vaccines prevent transmission of the coronavirus or mainly just protect against illness is still largely unknown. If the latter, achieving herd immunity through immunization becomes a difficult prospect.

While the good news that a coronavirus vaccine could be available by late December 2020 should help boost our optimism about “returning to normal times” in a not-too-distant future, it is imperative that we continue to follow COVID-19 safety guidelines and remain vigilant about the risks posed by the pandemic.  Indeed, as noted by Dr. Tedros Adhanom Ghebreyesus, WHO Director-General, “while a vaccine will be essential for bringing the pandemic under control, it is important to emphasize that a vaccine will complement the other tools that we have, not replace them.”  

Until vaccines become widely available, therefore, it should be clear to all that basic public health measures, such as disease surveillance, testing, contact tracing, medical isolation and quarantines, wearing masks in public spaces, social distancing, and hand hygiene, will continue to be our best firewall against the spread of the coronavirus and to save lives. 

Another key point to highlight, as shown in a recent study in Health Affairs, is that when it comes to cutting down on COVID-19 infections, hospitalizations, and deaths, a well-coordinated and timely deployment of vaccines matters just as much as their efficacy. So, as we discussed in a previous post, the urgent preparation for the massive deployment of the vaccine in the months to come is a public health, social, and economic imperative in countries across the world that cannot wait.