Over the last two weeks, four developers of a COVID-19 vaccine – out of more than 150 programmes currently engaged in a COVID-19 global vaccine race – published the successful results of Phase 1 clinical trials. The frontrunners in this race are: US Biotech firm Moderna, Oxford University with AstraZeneca and, last but not least, Chinese company CanSino and German biotech company BioNTech backed by US drug giant Pfizer.
How does it work? Principles of a vaccine and different types of vaccines
Different approaches to a vaccine
The whole idea behind a vaccine is to stimulate the body’s natural immune response to a virus by skipping it from its lethal characteristics and by giving the human body all the time needed to develop the right antibodies against the intrusive foreign organism.
As the New York Times explains there are basically three different approaches to a coronavirus vaccine.
- Inactivated / Attenuated Virus These vaccines are based on inactivated or weakened forms of the virus for which the vaccine is elaborated . This was the method used in the late XVIIIth to design the first vaccine and it has been generalised from the XIX to the late XXth century following the pioneering work of Jenner, Pasteur, Koch and many other scientists and doctors in their footsteps . Most of the conventional viruses for influenza and other common infectious diseases (measles, smallpox, ) are based on this prophylactic principle
- Non Replicating Viral Vector (NRVV): Basically this is a modern variant of the former approach as it uses another virus called adenovirus which has been modified with the gene of the coronavirus protein spike that needs to be inhibited. Hence it is more complex and requires some genetic engineering but it has proven to be effective for Ebola or HIV as of late.
- Viral Protein based vaccines: This approach is based on the injection of the protein spikes or fragments containing the incriminated proteins which stimulate the immune system to produce the counter-veiling antibodies
- Genetic vaccines (DNA, MRNA): These vaccines are based on the principle of inoculating the gene of the original virus responsible for the production of the spike protein. The human cells can then fabricate this protein either by building a Messenger RNA (MRNA) associated with injected DNA or by receiving directly the MRNA and the related “ready-to-use” instructions to manufacture the proteins. The immune system then detects these proteins and develops targeted antibodies. So far there are no human vaccines using this approach. Moderna’s vaccine candidate -MRNA 1273 – which is one of the four frontrunners outlined in the global race toward producing a COVID-19 vaccine – is an outstanding example of such an innovative approach.
Staggered clinical trials
After preclinical trials on animals, a vaccine has to go through three stages of clinical trials in humans as explained by GAVI:
- Phase 1 with a small number of volunteers 1 to test the vaccine’s safety and effectiveness
- Phase 2 with hundreds of participants split into groups such as children and elderly in randomised trials to further test safety and explore efficacy
- Phase 3 with thousands of participants to test whether there are any rare side effects that only show up in large groups, and also to test how effective the vaccine is and what kind of immune reaction it triggers.
Traditionally, going through all of these phases can take up to a decade. They are conducted sequentially and following the successful completion of Phase 3 trials, the vaccine is submitted to the regulatory authorities for approval. However, the extraordinary health emergency situation associated with the coronavirus pandemic has accelerated the process as it prompted regulators across the world to streamline their review and approval procedures, in order to save lives and to contain the spread of the virus. The example of rVSV Ebola vaccine which was developed in less than 12 months in response to the West African Ebola outbreak in 2014/2015 shows that it is possible to accelerate vaccine development when there is an emergency.
Speeding up the review and approval process for a vaccine
In the European Union
In the European Union, the European Medicines Agency (EMA) has developed a Health threats plan describing how the Agency operates during an emerging health threat. The plan has been activated since the outburst of the coronavirus pandemic. As part of its response, the Agency will accelerate its regulatory procedures so that marketing authorisations of COVID-19 related medicines can be granted as soon as possible. In practice, the COVID-19 EMA pandemic Task Force (COVID-ETF) established by the EMA is in charge of coordinating and enabling fast regulatory action on the development, authorisation and safety monitoring of the COVID-19 treatments and vaccines.
EMA initiatives for acceleration of procedures for COVID-19 treatments and vaccines
According to the EU pharmaceutical legislation, the standard timeline for the evaluation of a medicine is a maximum of 210 active days. However, applications for marketing authorisation for COVID-19 products will be treated in an expedited manner:
- Rolling data submission and review. This procedure allows EMA to assess data for a promising medicine as they become available on a rolling basis. Under normal circumstances, all data supporting a marketing authorisation application must be submitted at the start of the evaluation procedure. In the case of a rolling review, CHMP rapporteurs are appointed whilst development is still ongoing and the Agency reviews data as they become available. Several rolling review cycles can be carried out during the evaluation of one product as data continue to emerge, with each cycle requiring around two weeks, depending on the amount of data to be assessed.
- Once the data package is considered complete, a developer submits a formal marketing authorisation application to EMA which is then processed under a shortened timetable.
- Accelerated assessment. This procedure can reduce the review time of products of major interest for public health from 210 days to less than 150 days.
In practice, assessment timelines will be reduced to the absolute minimum. The compliance checks will also be expedited.
In the United States
The Federal Drug Administraton
The Emergency Use Authorization (EUA) authority allows FDA to help strengthen the nation’s public health protections against CBRN threats by facilitating the availability and use of MCMs needed during public health emergencies.
Under section 564 of the Federal Food, Drug, and Cosmetic Act (FD&C Act), the FDA Commissioner may allow unapproved medical products or unapproved uses of approved medical products to be used in an emergency to diagnose, treat, or prevent serious or life-threatening diseases or conditions caused by CBRN threat agents when there are no adequate, approved, and available alternatives.Federal Drug Administration, About Emergency Use Authorizations
The FDA has also actioned its Accelerated Approval regulations instituted in 1992. These regulations allow drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate or an intermediate clinical endpoint. Using a surrogate endpoint enables the FDA to approve these drugs faster. As could be read on the dedicated section of the FDA website:
A surrogate endpoint used for accelerated approval is a marker – a laboratory measurement, radiographic image, physical sign or other measure that is thought to predict clinical benefit, but is not itself a measure of clinical benefit. Likewise, an intermediate clinical endpoint is a measure of a therapeutic effect that is considered reasonably likely to predict the clinical benefit of a drug, such as an effect on irreversible morbidity and mortality (IMM).
The FDA bases its decision on whether to accept the proposed surrogate or intermediate clinical endpoint on the scientific support for that endpoint.
The implementation of a rolling review and approval process by FDA, combined with rapid manufacturing, while the vaccine is still undergoing clinical trials, allows for a significant compression of the traditional timeline for drug development, which may extend over several years. figure below reproduced from a post dedicated to COVID-19 vaccines published on the WatchBlog of the US Government Accountability Office (GAO) shows the differences between traditional vaccine development and a potential accelerated timeline.
Coordination between regulators at the international level
In addition to these efforts to accelerate and facilitate the release of a vaccine on both sides of the Atlantic, Medicines regulators from around the world have been stepping up their collaboration to facilitate and expedite the development and evaluation of therapeutics, diagnostics and vaccines against COVID-19 through the International Coalition of Medicines Regulatory Authorities (ICMRA). As can be read following a workshop held by ICMRA on this topic on June 22. Phase III clinical trials for potential vaccines have to meet the following criteria:
- Phase 3 clinical trials should enroll many thousands of participants, including those with medical comorbidities, to generate relevant data for the key target populations
- Phase 3 clinical trials should assess the overall vaccine efficacy across subgroups enrolled. It was acknowledged that trials will not be powered to demonstrate vaccine efficacy by subgroup, e.g., importantly in individuals aged 75 and over
- Phase 3 clinical trials should be randomized, double-blind and controlled either using placebo or active comparator.
- Endpoints used in Phase 3 clinical trials should preferably be standardized across trials to allow vaccine effectiveness and safety comparison of different SARS-CoV-2 vaccine candidate. The primary endpoint should be laboratory-confirmed COVID-19 of any severity. Other important endpoints include SARS-CoV-2 infection monitored for and confirmed either by virologic methods, or by serologic methods evaluating antibodies to SARS-CoV-2 antigens not included in the vaccine, and severity of disease as measured by hospitalization, mechanical ventilation or death.
- Phase 3 clinical trials should also include interim analyses to assess risk of enhanced disease and futility.
- Initial efficacy trials should include efficacy point estimates that reflect the desired vaccine efficacy and specification of the lower bound of appropriately alpha-adjusted confidence interval around the primary efficacy endpoint point estimate.
The risks associated with an accelerated procedure
Accelerating vaccine development could result in less time spent on evaluating the safety of the vaccine. Some patients could experience serious adverse effects. Shortening the timeline could also mean that scientists learn less about the potential range of adverse effects.gao.gov
Moving quickly to authorize and distribute tests may increase risks associated with their accuracy. As a result, there is the potential that some tests could show patients have not been exposed to or infected by the virus that causes COVID-19 when they actually have beengao.gov
Availability of supplies / human resources
In addition, while tests may be developed quickly, their widespread use could be limited by the availability of supplies required to conduct testing safely, including swabs and personal protective equipment.gao.gov
The New England Journal of Medecine published an Editorial on July 14 on its website emphasising these risks and water-down expectations for the availability of a vaccine before the end of the year, following the publication in the Journal in the same day of positive findings from a Phase 1 trial initiated in April this year by biotechnology firm Moderna (MRNA) to evaluate the safety of its to evaluate an mRNA SARS-CoV-2 vaccine.
How extensive is the global effort to design a vaccine?
According to the WHO, Researchers around the world are currently developing more than 153 vaccines against the coronavirus in pre-clinical , of which 23 vaccines are in human trials. In the table below we list the later vaccines. The New York Times reviews all the ongoing development effort for vaccines in clinical stages on its COVID-19 vaccine tracker page.
|University of Oxford / Astra Zeneca
|Anhui Zhufeng / Institute of Microbiology, Chinese Academy of Sciences
|Cansino / Beijing Institute of Biotechnology
|Inovio Pharmaceuticals/ International Vaccine Institute
|Osaka University/ AnGes/ Takara Bio
|Cadila Healthcare Limited
|Wuhan Institute of Biological Products/Sinopharm
|Beijing Institute of Biological Products/Sinopharm
|Institute of Medical Biology , Chinese Academy of Medical Sciences
|Gamaleya Research Institut
|Clover Biopharmaceuticals Inc./GSK/Dynavax
|Vaxine Pty Ltd/Medytox
|University of Queensland/CSL/Seqirus
|Imperial College London
|People’s Liberation Army (PLA) Academy of Military Sciences/Walvax Biotech.
What is the expected release date for a COVID-19 vaccine?
Using historical data on clinical trials performed over the last twenty years, encompassing 2544 vaccine development programmes of which 814 (25%) where related to respiratory diseases – 1838 sponsored by industry and 706 without an industry sponsor in any stage of development -, Andrew Lo and his colleagues from the MIT estimated in a study published in April 2020 that the overall probability of success for an industry sponsored vaccine program hovered around 40%. They also found at that non-industry sponsored vaccine programs had a much lower probability of success, estimated to be around 7%. This may be explained partially by a selection bias as non-profit organisations -i.e. public research centers and NGOs – focus on projects that are less likely to be pursued by industry-sponsored vaccine developers. In any case, the trend is toward increased collaboration between the non-profit sector and industry players.
Actually, Andrew Lo and his colleagues found out that, based on historical data, the overall probability of success (PoS) for vaccines – from Phase 1 to Approval – is much higher than for any other class of drugs, as can be seen from the table below. On average, according to this study, 83.9% of all vaccines in Phase 1 transitioned to Phase 2. The success transition probability from Phase 2 to Phase 3 stood at 66.4% with a very low standard error. Once a drug made to Phase 3 it has a chance of 80% of being approved. These figures do not take into account the COVID-19 / SARS-COV-2 pandemic and the associated drug developments for SARS-COV-1 and MERS-COV. More generally, these results should be put in perspective, as there is no vaccine, as of yet, for diseases caused by agents in the biological families of retroviridae (e.g., HIV), caliciviridae (e.g., norovirus), clostridiaceae (e.g., clostridium difficile), coronaviridae (e.g., SARS, MERS), herpesviridae (e.g., CMV infection), or togaviridae (e.g., chikungunya).
Nevertheless, considering the relaxation of regulatory constraints in line with the health emergency situation, it could be argued that in the current context a COVID-19 vaccine candidate that successfully makes it to phase 3 has almost a 100% chance of being approved.
Given these estimates, the question that matters for investors is what happens once one firm gets approval for its vaccine. Are all the other efforts made useless? In practice, more than one vaccine is needed to address the needs of specific demographic groups.
How much will a COVID-19 vaccine cost?
Fairness and affordability vs. profitability
As Suerie Moon, Director of the Global Health Center The Graduate Institute, Geneva writes in the first issue of Global Challenges:
The tension between cooperative public health versus competitive geopolitical imperatives is playing out in the race to develop these health technologies and secure access to them. The strategic manoeuvrings of a wide cast of players highlights how science, industrial capacity and non-state actors are shaping the global order.Suerie Moon, The Vaccine Race: Will Public Health Prevail over Geopolitics?, Global Challenges, Issue 1, June 2020.
She notes on an optimistic tones regarding Europe’s response to the pandemic that on the international level, Europe has emerged as a leader in promoting international cooperation and spearheading the global effort against the pandemic. In Moon’s own words:
The ability to hammer out an agreement bridging the concerns of the US, China and the pharmaceutical industry testifies to Europe’s efficacy as a broker of cooperation.
It is true that by pledging almost €10 billion to ensure global access to drugs, diagnostics and vaccines and by pleading for a balanced approach between intellectual property rights and public health considerations – acknowledging the primacy of the later over the former. Europe has been faithful to its reputation as a posterchild of multilateralism as opposed to the Trump’s Administration unabashed embrace of unilateralism and to an increasingly assertive China that openly displays its ambitions of global leadership.