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The vaccine race

With more than 150 COVID-19 vaccines in development, we put the three front-runners under the microscope and look at the incredible, unprecedented development work of the last year.

On 9 November 2020, as Europe was grappling with the second wave of the COVID pandemic, a little glimmer of hope appeared, following the announcement by New York-based Pfizer and German pharmaceutical company BioNTech. They made history by declaring that the vaccine they were developing against COVID-19 was over 90% effective, according to preliminary data.

A week later, US biotech company Moderna reported similar findings with a similar vaccine. Then, pharmaceutical group AstraZeneca and the University of Oxford followed in their footsteps – they released positive results about their COVID-19 vaccine, saying it had 70% efficacy, after clinical trials conducted in the UK and in Brazil.

For the first time since the SARS-CoV-2 pandemic broke out, the possibility of containing it with safe and effective vaccines seemed to materialise.

The last year has been a turning point for the scientific community. More exposed to public scrutiny than ever, researchers have had to work under intense pressure and at great speed to gain a better understanding of a virus and a disease that had been unknown to them before. Vaccine research in particular has been very dynamic. Hundreds of teams around the world have joined in the efforts to develop and test suitable vaccine candidates in preclinical models and in clinical trials.

According to the World Health Organization (WHO), as of 12 November 2020, 48 vaccines had reached the stage of clinical trials on humans, and at least 164 preclinical vaccines were under active investigation in vitro and in animal models.

While Pfizer/BioNtech, Moderna and AstraZeneca/Oxford are the first groups to come up with preliminary efficacy results, and following the UK approval of the Pfizer/BioNTech vaccine regulatory agencies in some other countries are expected to approve their vaccines by early 2021, pursuing research efforts remains a priority. The hope is that different options will become available in coming months, in order to vaccinate larger numbers of people worldwide, in a safe and effective way. Having multiple licensed vaccines may also allow countries to establish simpler vaccination strategies for their populations and for cheaper products to emerge.

Unprecedented speed and scale

The COVID-19 global vaccine research effort is unprecedented in terms of both scale and speed. Vaccines are usually developed over many years, getting approval by regulatory agencies after rigorous stages of testing that can last long periods.

The traditional development pathway lasts, on average, a decade.

Developing a vaccine against COVID-19 in a year represents a fundamental step-change from the traditional vaccine development, even compared with the accelerated five-year timescale for the development of the first Ebola vaccine. These unprecedented research efforts to develop, test and roll out a COVID-19 vaccine have been associated with new and original vaccine development paradigms involving parallel and adaptive development phases, innovative regulatory processes and scaling manufacturing capacity.

The intensity of the pandemic also means that the virus was rife in the population at the time of the trials, so it did not take long for volunteers to be exposed to SARS-CoV-2 and for scientists to get data on the vaccine’s efficacy. “There have been some innovative and adaptive trial designs, which allow accelerated development whilst maintaining rigour. The high incidence of COVID-19 makes the measurement of trial endpoints feasible”, says Raina MacIntyre, a Professor of Biosecurity and expert of infectious diseases at the University of New South Wales.

There has been unprecedented availability of scientific and financial resources

Some of the teams working on vaccine development were also able to get a headstart, thanks to previous research on coronaviruses. Moderna had, for example, previously collaborated with the NIH on a vaccine for a different type of coronavirus, MERS-CoV, which remains active in the Middle East. While that programme was only at the research stage, it provided significant insights to develop the mRNA-1273 vaccine against SARS-CoV-2.

“When companies take on the development of a vaccine, they need logical and economic reasons to do so. While the research on MERS-CoV had gone far ahead at the time, it has not yet materialised into commercialised vaccines. The speed of vaccine development this year has mostly to do with an unprecedented availability of scientific and financial resources”, says Sanjay Mishra, Staff Scientist at Vanderbilt University Medical Centre, 
who has written on the new vaccines.

mRNA-1273 Moderna 
About the vaccine: Moderna’s vaccine is an RNA vaccine. The group had already worked on this technology before with successful early-stage (Phase I) clinical trials against five other respiratory viruses (two pandemic influenza strains, RSV, hMPV, and PIV3). Over the last four years, the company has started nine clinical trials for mRNA vaccines. This expertise has allowed them to respond quickly to the COVID-19 pandemic.

Phase III trial: Known as COVE, it enrolled more than 30,000 participants at 100 clinical research sites in the US. It launched on 27 July 2020 after results from earlier-stage clinical testing indicated that the vaccine candidate is well tolerated and immunogenic. The researchers sought to enrol a diverse pool of participants and indeed, 37% of trial volunteers are from racial and ethnic minorities.

Results: The interim review of the trial’s data suggests that the vaccine is safe and effective at preventing symptomatic COVID-19 in adults. It notes a vaccine efficacy rate of 94.5%. In total, 95 cases of COVID occurred among participants. In total, 90 of the cases occurred in the placebo group and five occurred in the vaccinated group. There were 11 cases of severe COVID-19 out of the 95 total, all of which occurred in the placebo group.

BNT162b2 Pfizer/BioNTech

About the vaccine: This candidate is also an RNA vaccine composed of nucleoside-modified mRNA encoding a mutated form of the spike protein for SARS-CoV-2. It is formulated in lipid nanoparticles and given via intramuscular injection.

Phase III trial: Phase III of the clinical trial began on 27 July and has enrolled 43,538 participants to date in centres across the world, including the US. On 8 November 2020, 38,955 had received a second dose of the vaccine candidate. Approximately 42% of global participants and 30% of US participants have racially and ethnically diverse backgrounds.

Results: The first interim efficacy analysis suggested this vaccine candidate is more than 90% effective in preventing COVID-19 in participants without evidence of prior SARS-CoV-2. The analysis evaluated 94 confirmed cases of COVID-19 in trial participants. No serious safety concerns were observed. The trial is expected to continue through to final analysis at 164 confirmed cases in order to collect further data and characterise the vaccine candidate’s performance against other study endpoints. 

AZD1222 AstraZeneca/Oxford

About the vaccine: AZD1222 is made from a virus (ChAdOx1), which is a weakened version of a common cold virus that causes infections in chimpanzees. This virus has been genetically changed so that it is impossible for it to grow in humans. Genetic material has been added to the ChAdOx1 construct, which is used to make the spike proteins.

The trials: The analysis included data from the COV002 Phase II/III trial in the UK and COV003 Phase III trial in Brazil. Investigators follow over 23,000 participants who received two doses of either a half-dose/full-dose regimen or a regimen of two full doses of AZD1222 or a comparator, meningococcal conjugate vaccine or saline. Participants are aged 18 years or over from diverse racial and geographic groups. Clinical trials are also happening in the US, Japan, Russia, South Africa, Kenya and Latin America, and more studies are planned in other European and Asian countries. The goal is to enrol up to 60,000 participants globally.

Results: So far, they have been able to show that one dosing regimen showed vaccine efficacy of 90% when AZD1222 was given as a half-dose, followed by a full dose at least one month apart, and another dosing regimen showed 62% efficacy when given as two full doses at least one month apart. The combined analysis from both dosing regimens resulted in an average efficacy of 70%. 

Diverse technology platforms

The different vaccine candidates under investigation, including the products developed by the three front-runners, rely on diverse vaccine technologies. These approaches include nucleic acid (DNA and RNA) vaccination, virus-like particle, peptide, viral vector (replicating and non-replicating), recombinant protein, live attenuated virus and inactivated virus approaches. Many of these platforms are not currently the basis for licensed vaccines available for other diseases, but experience in other medical fields, such as oncology, is helping to promote innovative next-generation approaches.

Both Moderna and Pfizer/BioNTech have developed a novel type of vaccine made from messenger RNA, known as mRNA. This technology offers great flexibility in terms of antigen manipulation and potential for speed. Until now, however, no licensed vaccines had relied on it.

Vaccines traditionally contain either weakened viruses or purified signature proteins of the virus, but mRNA vaccines are different. People are injected with genetic material – mRNA – that encodes the viral protein. Their cells use the information in that material to create a protein (in this case, a version of the spike protein from SARS-CoV-2). The idea behind this strategy is to mimic what the virus does in nature – but mRNA codes only for the critical fragment of the viral protein. This gives the immune system a preview of what the real virus looks like and trains it to respond to an infection without causing disease.

AstraZeneca/Oxford on the other hand is relying on a more traditional strategy. Known as AZD1222, their vaccine uses a replication-deficient viral vector based on a weakened version of a common cold virus that causes infections in chimpanzees and contains the genetic material of the SARS-CoV-2 virus spike protein. After vaccination, the body produces the surface spike protein, priming the immune system to attack the SARS-CoV-2 virus in the case of an infection. “These are not the only vaccines under development,” Sanjay Mishra points out. “They’re the ones that have been made the fastest, but it does not mean that other trials will not be as effective. Most of the other studies also focus on the spike protein of the virus, and will probably yield equally good outcomes. Afterwards, it will be up to each country to approve each vaccine available for their region depending on what’s available to them, what their resources are, and based on data on efficacy and safety.”

Concerns and transparency

Preliminary results announced by the three companies are promising. However, some questions remain, as the data made public so far only gives us an idea of the vaccine candidates’ efficacy, roughly three months after injection. Raina MacIntyre says: “I would not put too much stock on the comparative efficacy between the different vaccines which have provided efficacy estimates at this stage, because they would reflect very short-term follow up – at the most, the only available data at this stage would be efficacy at one to three months post-dose one.

“No trial would have data beyond six months post-vaccination, because the earliest Phase III trials commenced in April. The more important question is what is the efficacy at 12 months, 24 months and 36 months? We also need to know that efficacy endpoints are the same when comparing vaccines – for example, PCR-confirmed infection, serologically confirmed infection, hospitalisation or death. We need longer term follow-up data.” Seeing the data transparently published in peer-reviewed journals will also be crucial, in order to start answering some of these questions, build appropriate public health policies and vaccination strategies and to start addressing some of the concerns that patients may have regarding the vaccines.

The announcements by Pfizer/BioNTech, AstraZeneca/Oxford and Moderna, followed by the start of mass vaccination in the UK, represent huge steps forward, but they are only the beginning of the COVID-19 vaccination story.   

Key dates in the Covid-19 vaccine race     

  • 11 January 2020: Chinese authorities share the genetic sequence of the novel coronavirus.     
  • 24 February 2020: Moderna shipped the first clinical batch of mRNA-1273 to the NIH for use in their Phase I clinical study.     
  • 27 July 2020: Start of Moderna Phase III study of mRNA-1273 in collaboration with the NIH. The Pfizer/BioNTech Phase III trial also starts on that day.     
  • July 2020: Trump administration awards a $1.9bn contract in July to Pfizer/BioNTech for 100 million doses.     
  • August 2020: The European Union reaches an agreement with AstraZeneca. The company will deliver 400 million doses, if the trials yield positive results.     
  • 9 November 2020: Pfizer/BioNTech announces the Phase III preliminary results of its clinical efficacy trial.     
  • 16 November 2020: Moderna announces the Phase III preliminary results of its clinical efficacy trial.     
  • 20 November: Pfizer submits a request for an emergency use authorisation.     
  • 23 November 2020: AstraZeneca announces its own Phase III preliminary results.     
  • 1 December 2020: The EMA received an application for conditional marketing authorisation for the BioNTech and Pfizer vaccine.     
  • 2 December 2020: UK is the first country to approve the Pfizer and BioNTech vaccine for widespread use.

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