Since the World Health Organization (WHO) declared the COVID-19 pandemic in March 2020, researchers all over the world have joined the race for an effective vaccine. Here is how the search for a vaccine progressed throughout the year.

March 11, 2020, is a day that many of us will remember for years to come. That is when the WHO declared that the epidemic of infections with a previously undescribed human coronavirus, SARS-CoV-2, had spread globally, qualifying as a pandemic.

Since then, the world’s countries have cycled through restrictive measures — ranging from physical distancing to full lockdowns — to try to keep the spread of the new coronavirus in check.

Throughout this period of anxiety and uncertainty, scientists and members of the public alike have shared one mantra: The pandemic will subside once there is a commonly available vaccine against COVID-19, which is the respiratory disease caused by SARS-CoV-2.

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At the time of this feature’s publication, five vaccines have received authorization from different countries around the world as safe and effective against COVID-19.

How did we get here in 9 months? What routes did the science world take in the search for viable vaccines? In this Special Feature, we look at the vaccine research highlights from March to December 2020.

Spring: The start of COVID-19 vaccine research

Even before the WHO declared the emergence of a pandemic, scientists had started looking for vaccine and therapeutic targets.

In early March, researchers from Germany and the United States had already submitted papers to the journal Cell discussing potential mechanisms that might prevent infections with SARS-CoV-2.

Their laboratory and animal research then suggested that SARS-CoV antibodies might help block the virus’s entry into healthy cells, thus potentially reducing infections.

In mid-March, researchers from the National Institutes of Health (NIH) and the biotechnology company Moderna also started enrolling the first volunteers to trial what has now become known as “the Moderna vaccine.”

The Moderna vaccine uses a relatively new technology that introduces genetic information about the virus into our cells to “train” the immune system to recognize and react to SARS-CoV-2. This type of vaccine is known as an mRNA vaccine.

At that point, the NIH and Moderna were testing primarily for safety, to make sure that their vaccine candidate did not have major unwanted effects on health.

In April, researchers from the University of Oxford in the United Kingdom and the biopharmaceutical company AstraZeneca started trials for their own vaccine candidate, now known as “the Oxford vaccine” or “AstraZeneca vaccine.”

Their research group used a weakened chimpanzee adenovirus, which is a common cold virus, to stimulate the immune system and to deliver the genetic code for our cells to make the SARS-CoV-2 spike protein. This protein allows the new coronavirus to enter and infect our cells.

By delivering this protein in viral particles that cannot cause disease, the researcher’s aim was to safely introduce it into the human body to “teach” the immune system to react to SARS-CoV-2, should it have exposure to this virus.

At that point, the scientists from the University of Oxford and AstraZeneca were hopeful that their vaccine would prove safe and effective and receive approval for public immunization programs by fall 2020.

A Chinese vaccine candidate also caught the attention of public health experts in April. That month, researchers from the Chinese biotechnology company Sinovac Biotech tested a vaccine containing inactivated SARS-CoV-2 in rhesus macaques.

“What I like most [about this type of vaccine] is that many vaccine producers, also in lower-middle income countries, could make such a vaccine,” said Prof. Florian Krammer, a specialist in immunology and virology from the Icahn School of Medicine at Mount Sinai in New York City, NY. Prof. Krammer was not involved in this research.

In May, the Oxford vaccine was already entering phase 2 trials in humans. These trials aimed to find out if the vaccine would affect immune systems differently depending on the participants’ ages.

Also, researchers from the pharmaceutical corporation Pfizer and the biotechnology company BioNTech started phase 1 trials, or safety trials, in humans for their own mRNA vaccine candidate.

Pfizer representatives expressed satisfaction with the short time it took them to take the vaccine candidate from proof of concept to human trials.

Dr. Albert Bourla, chairman and CEO of the pharmaceutical corporation, declared that:

“The short, less-than-4-month timeframe in which we’ve been able to move from preclinical studies to human testing is extraordinary and further demonstrates our commitment to dedicating our best-in-class resources, from the lab to manufacturing and beyond, in the battle against COVID-19.”

Also in May, scientists from the China National Institute for Food and Drug Control in Beijing, the Beijing Institute of Biotechnology, and the vaccine company CanSino Biologics published the results of the phase 1 trial of yet another vaccine candidate.

Their candidate used an adenovirus that is no longer able to replicate, which carries the SARS-CoV-2 spike protein on its surface.

According to the researchers, the vaccine candidate was well tolerated at that point. When side effects did occur, they tended to be mild.

The investigators also reported signs that their vaccine candidate might be effective in fighting SARS-CoV-2.

According to lead researcher Prof. Wei Chen, from the Beijing Institute of Biotechnology in Beijing, “The trial demonstrates that a single dose of the new vaccine [candidate] produces virus-specific antibodies and T cells in 14 days, making it a potential candidate for further investigation.”

Summer: The race against time continues

In June, Sinovac had made public preliminary reports that their vaccine candidate, known as CoronaVac, was safe, according to phase 1 and 2 trials in humans. Since then, Sinovac experts have published the finalized report in The Lancet: Infectious Diseases.

By mid-July, the Oxford vaccine was already showing promise. All of the participants who received the vaccine candidate in phase 1 had developed SARS-CoV-2-neutralizing antibodies, suggesting that it would be effective in preventing the development of COVID-19.

Prof. Andrew Pollard, a specialist in vaccinology and the chief investigator in the Oxford vaccine trial, also noted that the vaccine might work best if healthcare professionals delivered it in two doses:

“We saw the strongest immune response in participants who received two doses of the vaccine, indicating that this might be a good strategy for vaccination.”

That same month, Sinovac launched a phase 3 trial of their vaccine candidate in collaboration with Instituto Butantan in Brazil.

CanSino also published promising results after their phase 2 trial, which found that at 28 days after inoculation, a large majority of the trial participants demonstrated T cell responses. This consolidated suggestions that the vaccine candidate might be effective against SARS-CoV-2.

In August, Pfizer and BioNTech also published early data from phase 1 and 2 trials of their mRNA vaccine candidate. The results confirmed the vaccine candidate’s safety, and the researchers noted that any side effects were mild and short term.

An increase in antibodies following inoculation also suggested that the vaccine candidate might be effective in fighting SARS-CoV-2. The researchers went as far as to call the immune response they observed in participants “robust.”

These promising results propelled Pfizer and BioNTech toward the phase 3 trial, as the team suggested in the study paper.

“The clinical findings for the […] vaccine candidate are encouraging and strongly support accelerated clinical development, including efficacy testing, and at-risk manufacturing to maximize the opportunity for the rapid production of a SARS-CoV-2 vaccine to prevent COVID-19,” the authors wrote.

Fall and winter: When will the pandemic end?

By the beginning of September, Russian scientists had published the results of their own phase 1 and 2 trials testing the safety and immune response-inducing potential of yet another top candidate: the so-called Sputnik V vaccine.

Sputnik V also uses an adenovirus as a “base” that delivers the genetic code that allows our cells to make the SARS-CoV-2 spike protein. It then uses a different adenovirus with the Spike protein to deliver a second booster dose. According to its developers, the initial trial data indicated that their product was both safe and potentially effective in stopping the virus in its tracks.

Following these promising results, the Russian government approved its use, despite the fact that the researchers had not yet conducted a phase 3 trial at that point.

This and the fact that the studies were open-labeled and non-randomized — two key requirements in obtaining strong, credible results — prompted doubts about Sputnik V’s viability among the international scientific community.

At the start of September, Oxford and AstraZeneca announced that their vaccine candidate was entering phase 3 trials in the U.S. However, these were briefly halted following concerns about one participant experiencing ill health.

Shortly thereafter, Gamaleya — the developers of the Sputnik V vaccine — also reported that their interim data suggested that their vaccine was more than 90% effective in preventing COVID-19.

On November 9, Pfizer and BioNTech announced that their vaccine was “more than 90% effective” if they delivered it in a two-dose approach.

“This is a victory for innovation, science, and a global collaborative effort,” said Prof. Uğur Şahin, the co-founder and CEO of BioNTech.

On November 16, Moderna also issued a press release declaring that their mRNA vaccine candidate had demonstrated 94.5% efficacy, based on phase 3 trial data.

Following suit, Oxford and AstraZeneca then announced that their vaccine candidate was more than 70% effective in preventing COVID-19.

In December, various national authorities moved toward authorizing these vaccines for use.

On December 2, the U.K.’s Medicines and Healthcare products Regulatory Authority authorized the Pfizer vaccine for emergency use. The U.K. began vaccinations on December 8.

On December 11, the Food and Drug Administration (FDA) also issued an emergency use authorization (EUA) for the Pfizer vaccine. The first healthcare worker received it just 3 days later.

On December 18, the FDA also issued an EUA to Moderna for their COVID-19 vaccine.

On December 21, the European Commission granted authorization of the Pfizer vaccine across the European Union.

Earlier this month, the scientists behind the Oxford vaccine also published the interim results of some of their phase 3 trials. These results indicated that their vaccine has “acceptable safety” and is effective against COVID-19.

Where do we go from here?

Many members of the public have expressed concern about the short timeframe in which these vaccines and vaccine candidates have gone from preclinical research to the final stages of trials in humans.

The main concern is that scientists may have cut corners in their rush to bring a COVID-19 vaccine to the public.

However, researchers explain that their process was much quicker than usual not because they left out any of the required safety and efficacy testing, but because they were able to take more financial risks — thanks to international investments in their research.

In a talk they gave at WIRED Health: Tech in October, Dr. Tal Zaks, chief medical officer of Moderna Therapeutics, and Prof. Şahin explained that having access to more funding meant that they were able able to carry out their investigations faster, without worrying about the impact of loss of capital in the event that their vaccine candidates did not pass safety or efficacy trials.

Prof. Şahin explained:

“One important aspect is that instead of skipping [steps] or cutting corners, we decided to do things in parallel. Usually, [in] vaccine development […] you do a phase 1 study, and maybe 6 or 12 months later a phase 2 study, and then decide whether you would do a phase 3 study. This is based on minimizing the cost risk but also based on the traditional way [in which a vaccine] is developed. It is not the best way — it is just the traditional way.”

Dr. Zaks and Prof. Şahin also emphasized how important open collaborations between research institutions and pharmaceutical companies had been in ensuring fast progress in identifying viable vaccines.

“The way [in which] the whole industry developed vaccines against COVID-19 […] is the best performance of collaboration,” said Prof. Şahin, while Dr. Zaks added that “the world needs more than one company to succeed” in their search for a vaccine.

At the moment, the vaccines with authorizations are gradually being distributed to those most at risk of COVID-19, such as healthcare workers and older adults.

The search for more viable vaccines continues, and specialists in public healthcare are considering the best ways to maximize the positive impact of the available vaccines.

For now, during the first phase of global rollout, around 3% of available vaccine doses are likely to reach health and social care workers, and around 17% will probably reach other adults at high risk of COVID-19. This is according to projections cited by Dr. Alba María Ropero Álvarez, who is the Pan American Health Organization regional advisor on immunization, at a webinar in October.

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