SCIENCE3 - The Miracle of COVID-19 Vaccines

The current COVID-19 pandemic apparently started in the Wuhan region of China in December 2019, and by early 2020, had spread to all continents (except Antarctica), leading to almost 120 million people infected and over 2.6 million deaths, at the time of this writing.  Also, in early 2020, a world-wide effort began to develop a vaccine to prevent COVID-19 infections - a miraculous effort that in less than a year - in record time - produced two 95%-effective vaccines, with vaccination efforts beginning in the U.S. in late December 2020.  

This is the story of COVID-19 vaccine development.  I will cover a description of COVD-19 characteristics, the research over the last 25 years that enabled such rapid development of a vaccine, the development timeline for the principal two U.S.-approved vaccines, other vaccines available or in development, the potential benefit to future vaccines of the recent stupendous efforts, and a snapshot of COVID-19 infections, deaths, and vaccinations.

I will concentrate on the Pfizer and Moderna vaccines since they were the first to be developed and approved for general use in the U.S.

My principal sources for this article were “The lightning-fast quest for COVID vaccines - and what it means for other diseases,” at nature.com; “Race to the Vaccine,” at usatoday.com; “A timeline of COVID-19 Vaccine Development,” from the Center for Disease Control and Prevention; “Vaccines in Development,” from the COVID-19-real-time-learning-network - plus numerous other online resources.

COVID-19 Characteristics

Coronaviruses are a family of infectious viruses that can cause respiratory illness in humans.  There are many different kinds of coronaviruses.  Some of them can cause colds or other mild respiratory (nose, throat, lung) illnesses.  Other coronaviruses can cause more serious diseases, including severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).  Coronaviruses are named for their appearance:  Under the microscope, the viruses look like they are covered with pointed structures that surround them like a corona, or crown.

The new strain of coronavirus was first reported in Wuhan, China in December 2019.  On February 11, 2020 the World Health Organization announced the official name for this disease: coronavirus disease 2019, abbreviated as COVID-19.  In COVID-19, “CO” stands for corona, “VI” for virus, and “D” for disease.   The virus that causes the disease COVID 19 is called severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The World Health Organization declared the outbreak a Public Health Emergency of International Concern on January 30, 2020, and a pandemic on March 11, 2020.

Most people infected with the COVID-19 virus will experience mild to moderate respiratory illness and recover without requiring special treatment.  Older people, and those with underlying medical problems like cardiovascular disease, diabetes, chronic respiratory disease, cancer, and obesity are more likely to develop serious illness.

The COVID-19 virus spreads primarily through droplets of saliva or discharge from the nose when an infected person coughs or sneezes.

 

This illustration from an electron microscope view, created at the Center for Disease Control and Prevention (CDC), reveals the structure of coronaviruses.  Note the spikes that adorn the outer surface of the virus, which impart the look of a corona.

 

Earlier Research

The research that helped to develop vaccines against the new coronavirus started well before COVID-19 was identified.  For years, researchers had been paying attention to related coronaviruses, which cause SARS and MERS, and some had been working on new kinds of vaccines - an effort that was now to pay off spectacularly.

Conventional vaccines contain disabled forms of the virus itself, which stimulate the body’s immune defenses against infection by a live virus.

But a new approach, based on RNA technology, had been under investigation for at least 25 years and matured just at the right time; five years ago, RNA technology would not have been ready.

RNA, ribonucleic acid, is a nucleic acid present in all living cells.  Its principal role is to act as a messenger carrying instructions for controlling the synthesis of proteins.  In a vaccine, RNA, in a modified form called messenger RNA or mRNA, is encased in a fat bubble and injected into a person’s arm.  It produces a protein identical to the protein on the surface of the virus.  That foreign molecule protein triggers an immune response without having to use actual bits of the virus.

The concept of modifying the elements of RNA to slip past the immune system, was first developed by Katalin Karikó and Drew Weissman at the University of Pennsylvania; their findings were published in the journal Immunity in 2005.  The modifications Karikó and Weissman developed allowed RNA to become a promising delivery system for both vaccines and drugs.  To be sure, their work was enhanced by scientists at Moderna, BioNTech and other laboratories over the past decade.  Their discovery would turn out to be a key element in speeding up the development of a COVID-19 vaccine, allowing scientists to dramatically accelerate the time usually needed to develop a vaccine, which previously took several years.

 

Katalin Kariko and Drew Weissman, at the University of Pennsylvania, developed the concept of RNA modification.

Meanwhile, Barny Graham, in recent years Deputy Director of the National Institutes of Health’s Vaccine Research Center, and his colleagues, had been developing a way to use RNA technology to produce viral proteins to fight coronavirus diseases, and had invented a process to make a vaccine fast enough to stop a pandemic.  In December 2019, Graham was looking for a good virus candidate to test his team’s approach. 

 

Barney Graham, Deputy Director of the Vaccine Research Center, at the National Institutes of Health, led the development of corona virus proteins and a speedy vaccine production process.

 

U.S. Vaccine Development Timeline

On January 10, 2020, Chinese scientists posted the genetic sequence for what they called the “Wuhan seafood market pneumonia virus.”  It was a novel coronavirus, SARS-CoV-2, a new version of a family of infectious diseases.

Worldwide efforts to come up with a vaccine began immediately.  Pfizer/BioNTech and Moderna had a big head start, having experimented on viruses for years, and were poised to apply the matured mRNA technology to vaccines.  They moved quickly, but carefully; the more accurate they were, the more effective the vaccine would be.  With the new virus identified, it took both teams only a matter of days to design a vaccine.

When scientists began seeking a vaccine for the SARS-CoV-2 coronavirus in early 2020, they were careful not to promise quick success. The fastest any vaccine had previously been developed, from viral sampling to approval, was four years, for mumps in the 1960s.

The slowest part of vaccine development isn’t finding candidate treatments, but testing them. This often takes years, with companies running performance and adverse effects tests on animals and then in humans.  Human testing requires three phases that involve increasing numbers of people and proportionately escalating costs.  The COVID-19 vaccines would go through the same trials, but the billions of dollars poured into the process made it possible for companies to take financial risks by running some tests at the same time.

In January 2020, German biotech-company BioNTech started its program “Project Lightspeed” to develop a vaccine against the new COVID‑19 virus based on its already established mRNA-technology.  Phase I/II Trials were started in Germany on April 23^rd and in the U.S. on May 4^th, with four vaccine candidates entering clinical testing.  The initial pivotal Phase II/III Trial with the lead vaccine candidate began in July.

On March 30^th, the U.S. Department of Health & Human Services (HHS) started a program they coined “Operation Warp Speed,” (OWS) in an attempt to expedite a COVID-19 vaccine.  The crucial piece of OWS, beyond allocating hefty funds for vaccine research and development, was that it fundamentally changed how pharmaceutical and biotechnology companies assessed the risk of conducting large-scale clinical trials on a brand-new vaccine. This was achieved through the HHS building the requisite infrastructure and guaranteeing the manufacturing of any successful vaccine candidates. They also purchased allotments of the vaccines prior to knowing whether they would be successful.

 

Barney Graham talks to President Donald Trump during a visit in March.  Scientists at the Vaccine Research Center, co-led by Kizzmekia Corbett (far right), created RNA sequences for COVID-19 vaccines in early January.

By mid-summer, Moderna, cooperating with the National Institute of Heath, and Pfizer, with German biotech firm BioNTech, had established themselves as the leaders in the race to develop a COVID-19 vaccine.  Both companies took the mRNA vaccine approach, publishing initial Phase I/II clinical trial data on July 14^th for Moderna, and on August 12^th for Pfizer.  Although sample sizes were small - as they typically are in early phase clinical trials - the results demonstrated promising safety measures and antibody production against the protein from those who got the vaccine.

During this timeframe, both companies also published promising efficacy data in non-human primates. Both the Moderna and the Pfizer vaccines proved to be effective against infection in the vaccinated animals, allowing them to mount substantial responses against the virus.

Given these promising results, Phase III trials immediately began, with Moderna focusing their efforts within the U.S., and Pfizer/BioNTech taking a more global approach.  Between the two trials, more than 70,000 people received either a placebo or a real vaccine and were subsequently sent out into the real world where their COVID-19 status was monitored for approximately 10 weeks.

The Phase III results were published on 18 November 2020.  Both companies’ vaccines were found to reduce the risk of being infected with COVID-19 by a stunning 94-95%.

Both Pfizer/BioNTech and Moderna took these results to the U.S. Food and Drug Administration (FDA) for Emergency Use Authorization.  Typically, the FDA spends months analyzing data to approve a vaccine. This time, that work was done in 2-3 weeks, partly because the vaccines were so extraordinarily effective. (In advance, the FDA had said it was willing to give the green light to a vaccine that was 50% effective.)  On December 11^th, the FDA approved the Pfizer/BioNTech vaccine for emergency use, followed a week later on December 18^th, by approval for emergency use of the Moderna vaccine.

 

Rapid timeline for Pfizer/BioNTech vaccine development.

Comparative historic timelines for vaccine development - highlighting the amazingly fast development of vaccines against COVID-19.

 

 

Following FDA approval for emergency use, the U.S. immediately began aggressive production, distribution, and inoculation efforts with the Moderna and Pfizer/BioNTech vaccines, the first mRNA vaccines to be used in humans outside of clinical trials.  In addition, several other countries have started administering the Moderna and Pfizer COVID-19 vaccines.

Other COVID-19 Vaccines

COVID-19 vaccine development is continuing today at an aggressive pace.  Besides the Pfizer/BioNTech and Moderna vaccines, the U.S./Netherlands Johnson & Johnson COVID-19 vaccine has been approved by the FDA for emergency use in the U.S.  Internationally, appropriate national regulatory authorities have approved emergency or full use of four Chinese vaccines, three Russian vaccines, one UK/Sweden vaccine, and one vaccine from India. In addition, over a dozen other countries have COVID-19 vaccines in development.

The world was able to develop COVID-19 vaccines so quickly because of years of previous research on related viruses and faster ways to manufacture vaccines, enormous funding that allowed firms to run multiple trials in parallel, and regulators moving more quickly than normal.  Some of those factors might translate to other vaccine efforts, particularly speedier manufacturing platforms.

Benefit for Future Vaccines 

The COVID-19 pandemic should produce some permanent changes in vaccine development.  For a start, it might establish the use of mRNA vaccines - which hadn’t previously been approved for general use in people - as a speedy approach for other diseases.

Some scientists say that RNA technology is revolutionizing vaccinology.  Candidate mRNA vaccines can be chemically synthesized in a few days, in contrast to the more complicated biotechnology involved in producing proteins in cells. The technology lends itself to the nimble plug-and-play approach that will be required to respond to [future] pandemics.  RNA also simplifies manufacturing a lot.  You can use the same facility to make RNA for different diseases. That decreases the investment required. 

COVID-19 Snapshot

Shown below are graphs from the New York Times that track the number of worldwide and U.S. COVID-19 cases to date, along with the number of deaths, and trend data.  Safety practices such as wearing masks, social distancing, frequently washing hands, working from home, avoiding crowds, and now vaccinations seem to be turning the tide, although there is significant concern about some people’s willingness to be vaccinated and new variants of COVID-19.  To date, the total number of fully vaccinated people worldwide is 73.1M, with the U.S. accounting for 32.9M.

 

 

 

As of March 9^th, on the one-year anniversary of WHO declaring COVID-19 a global pandemic, Pat and I are fully vaccinated with both doses of the Moderna vaccine and very happy to have received them.  We were particularly impressed with the organization, effectiveness, and friendliness of our local vaccination providers in Tucson.  Stepping back, and reflecting on the last year and quarter or so, and remembering the political turmoil, inconsistent information, and serious delays, etc., we still consider the successful development and application of COVID-19 vaccines in such a short time to be a miracle.