Searching for the holy grail: A COVID-19 vaccine update
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Until we have mass immunity to COVID-19, the world cannot fully relax – both psychologically and practically.
Immunity can happen in two ways, each with its own costs:
- We develop herd immunity by allowing the disease to run its course, which carries with it a significant cost in excess mortality.
- We develop a vaccine and deploy it on a mass scale which also has various economic and social considerations.
There are many encouraging signs in the development of a COVID-19 vaccine, with numerous parallel studies underway and accelerated support for trials and regulatory approval. Generous funding is flowing from government, non-government and commercial sources accompanied by an unprecedented level of international cooperation.
However, vaccine development typically takes many years and individual trials have a low probability of success. Viruses are mutable and immunity may be short lived, although corona viruses are less susceptible to mutation than others. Vaccine production and distribution will take time, may become politicised and some may refuse vaccination. Different target groups, particularly the elderly, may require different doses and efficacy may also vary.
The generally accepted scientific view is the earliest we could expect a functional vaccine will be early to mid-2021, but the path to mass COVID-19 immunity may prove to be somewhat longer.
This article will review progress in the pursuit of a COVID-19 vaccine with a look at the most prominent vaccine candidates that are already in clinical trials and on a fast track. We'll review the platforms being used to develop a candidate vaccine, the expected timeline and the development of alternative immunotherapies.
Mass immunity to COVID-19, without enduring significant loss of life, can only fully be achieved through vaccine. Developing a safe vaccine for a new illness is neither easy nor straightforward. Under current best-case assumptions, it will take 12 to 18 months with an accelerated approval process and research moving at unprecedented speed.
Rapid progress is being made through concerted and coordinated efforts around the world. This includes China’s rapid sequencing of COVID-19 genetic material and subsequent global sharing of research, aided by substantial funding from private companies, governments and non-governmental organisations. The Coalition for Epidemic Preparedness Innovations (CEPI) has so far received government funding of USD 924 million toward a target of USD 2 billion for rapid investment and development of COVID-19 vaccine candidates.1,2 On 4 May, the World Health Organisation (WHO) organised a telethon to raise USD 8 billion from 40 countries to research, manufacture and distribute a possible vaccine and treatments for COVID-19.
From start to finish: developing a vaccine
Vaccine development normally requires two to five years before a clinical trial can begin. It's typical to have a three-step development process:
Step one: Pre-clinical studies
These typically involve laboratory and animal experiments, testing different strengths of the vaccine to find a dose that is safe, effective and non-toxic.
Step two: Clinical trials
Three phases of clinical testing are required prior to regulatory approval followed by a fourth phase of safety surveillance. Completing these stages can take years, even decades. However, COVID-19 clinical trials will be significantly accelerated.
- Phase 1: To confirm a vaccine is safe for humans, 50-100 “healthy” volunteers are tested. Some COVID-19 vaccine candidates are already in this phase.
- Phase 2: To assess preliminary efficacy, a few hundred volunteers participate in a “double blind” approach of randomised injections of either the vaccine candidate or a placebo. Neither testers nor those being tested are aware of which dose they are receiving.
- Phase 3: The vaccine candidate is tested in a few hundred to a few thousand volunteers against the best existing available treatment (which is not applicable for COVID-19) to confirm its efficacy and safety. Except in very rare circumstances, the approval of a drug or vaccine would not be granted without success in phases 2 and 3.
- Phase 4: Long-term post-approval surveillance on the safety, risks, benefits or best uses of the vaccine are compiled 3.
Step three: Regulatory approval
Official approval by the US Food and Drug Administration (FDA) or other equivalent national bodies will confirm the vaccine’s effects have been reviewed, and the treatment is determined to provide benefits that outweigh its known and potential risks in the intended population.
Given the urgent demand for a COVID-19 vaccine, clinical trials are being fast-tracked and likely to be carried out in parallel across different countries and age groups4. More than one vaccine may ultimately be released – each targeting a different group at risk, as is often done for the seasonal flu vaccine.
Platforms for vaccine development
There are many different paths to developing a vaccine – some new and others well established. The most prominent platforms in phase 1 COVID-19 trials stimulate human immune response in one of two ways:
- Using viral DNA and RNA molecules coding for parts of the target pathogen, or
- Using viral vectors (replicating or non-replicating) which are essentially harmless viruses that express a COVID-19 specific antigen – which triggers the immune response.
In both cases, the delivered antigens are subsequently displayed to the body's immune cells. Whereas platforms based on DNA and RNA offer great speed and flexibility for manipulating antigens, vaccines based on viral vectors are better for large-scale production capacity, long-term stability and induce strong immune responses.
Other platforms under development take a different approach and focus on viral elements that can be recognised by the immune system such as:
- short viral protein subunits
- rebuilt viral proteins
- weakened (attenuated) COVID-19 virus
- or inactivated versions of the COVID-19 virus
The attenuated or inactivated virus may generate a stronger and more durable immune response with minimal to no risk of infection.
What will the vaccine target?
Antigens are proteins on the virus wall, which allow the virus to invade cells or reproduce. They also serve as a target for the host's immune system. Detailed knowledge of specific COVID-19 antigen(s) is limited. Most pipeline vaccines aim to induce an immune response against the viral Spike (S) protein. The S protein allows the virus to invade a host cell by binding to the cell surface receptor angiotensin-converting enzyme 2 (ACE2), which is part of the renin-angiotensin system that controls blood pressure. However, it is still unclear how different forms and/or variants of the S protein used in different candidates relate to each other; and how strong immunity responses towards different antigens will be5.
There are concerns that excessive targeting of the S protein without enough focus on other structural elements of COVID-19 may cause the virus to mutate and lead to an immune exhaustion or immune escape. We already see a precedent for this in the influenza virus. Targeted antigens – haemaglutinin (H) and neuraminidase inhibitors(N) – mutate and lessen the effectiveness of the seasonal influenza vaccine.
Current COVID-19 vaccine candidate landscape
By early May 2020, there were more than 100 vaccine candidates at varying stages of development. The Vaccine Centre at the London School of Hygiene & Tropical Medicine currently lists 10 COVID-19 vaccine candidates in clinical trial phases 1 or 2 and another 110 candidates in exploratory or preclinical stages5–8.
The most advanced candidates include the six listed in the below summary. Of these it's notable that Moderna started clinical testing of its mRNA-based vaccine just two months after sequence identification of COVID-19 (see table, end of document).
Six of the most prominent targeted vaccines
1. mRNA-1273 from Moderna
An mRNA vaccine candidate encoding for a prefusion stabilised form of the S protein, which binds to the host cell. The S protein has been the target of vaccines against the coronaviruses responsible for Middle Eastern Respiratory Syndrome (MERS) and Severe Acute Respiratory Syndrome (SARS). The genetic sequence in COVID-19 is 80% similar to the S protein in SARS. The vaccine relies on mRNA to kickstart the endogenous production of proteins similar enough to the virus that they trigger the body’s adaptive immune system to produce antibodies effective against the real virus.
The active phase 1 clinical trial is designed to assess the safety, reactogenicity and immunogenicity of mRNA-1273 in 45 healthy males and non-pregnant females, ages 18-55. Estimated completion date is 1 June 2021.
The company hopes to enter phase 2 clinical trials by early summer 2020. Moderna may seek emergency authorisation for use of the vaccine and make it available to targeted groups such as healthcare professionals, possibly by the fall of this year9. However, there has never been an approved mRNA vaccine or other mRNA based therapeutics for any condition10.
2. Ad5-nCoV from CanSino Biologicals
A recombinant novel coronavirus vaccine that incorporates the adenovirus type 5 vector (Ad5) expressing the COVID-19 S protein. By mid-March the active phase 1 trial had enrolled 108 healthy subjects, ages 18-60. Results from preclinical animal studies showed that the vaccine candidate induced a strong immune response and demonstrated a good safety profile. Estimated primary completion date with trial data collection is the end of 2020.
A phase 2 clinical trial which started 12 April is currently recruiting 500 participants to further evaluate the immunogenicity and safety of Ad5-nCoV. Moving a vaccine from phase 1 to phase 2 in only three weeks is exceptionally fast. Phase 2 trial primary data is expected by January 20219.
3. ChAdOx1 nCoV-19 from the University of Oxford
Based on an adenovirus vector encoding for the S protein of COVID-19. The phase 1/2 clinical trial is recruiting approximately 500 healthy adult volunteers ages 18-55 to determine efficacy, safety and immunogenicity. Primary study completion is expected by May 2021. On 30 March, the University of Oxford and AstraZeneca announced an agreement for the global development and distribution of the vaccine if trials are successful.
4. INO-4800 from Inovio Pharmaceuticals
A DNA plasmid encoding the S protein and will be delivered by electroporation into human cells. Once inside the cell, the plasmids begin replicating, producing a specific immune response against COVID-19. The phase 1 clinical trial will evaluate the safety, tolerability and immunogenicity of INO-4800 in 40 healthy volunteers. Early results are expected by April 2021.
In parallel, the company is collaborating with the Korea National Institute of Health (KNIH) and running a phase 1/2 clinical trial in South Korea supported by an additional USD 6.9 million funding by CEPI. Furthermore, the company has entered into an agreement to expand its manufacturing partnership with the German contract manufacturer Richter-Helm BioLogics GmbH & Co. KG, to support large-scale manufacturing of the DNA vaccine.
5. LV-SMENP-DC from the Shenzhen Geno-Immune Medical Institute
A lentiviral vector expressing a synthetic minigene based on domains of selected viral structural proteins of COVID-19. The vaccine candidate under phase 1/2 evaluation is currently recruiting 100 patients to test its safety and efficacy. Estimated completion date of the study is 31 July 2023.
6. Pathogen-specific aAPC, from the Shenzhen Geno-Immune Medical Institute
Another lentiviral vector expressing viral proteins and immune modulatory genes to modify artificial antigen presenting cells (aAPC) and to activate T cells. The phase 1 trial will assess safety and immunogenicity in 100 participants with expected completion date by 31 July 2023.
Non-specific COVID-19 vaccines
In addition to COVID-19 targeted vaccines, other vaccines with non-specific effects are undergoing clinical evaluation. The anti-tuberculosis BCG vaccine is being tested for potential protective effect against COVID-19 in two phase 3 trials recruiting about 5,000 healthcare workers in the Netherlands and Australia. The trials are pursuant to assertions that COVID-19 mortality was lower in countries that have routine BCG vaccine administration11.
Numerous other companies and partnerships have plans to develop additional vaccine candidates, which are expected to enter clinical studies over the next couple of months12,13.
Global pharmaceutical collaborations
Several large pharmaceutical companies are collaborating on COVID-19 vaccine work. On March 30, Johnson & Johnson, Janssen Pharmaceutical and the Biomedical Advanced Research and Development Authority (BARDA) (which is part of the US Department of Health and Human Services), announced the selection of a lead COVID-19 vaccine candidate. The company expects to rapidly scale manufacturing capacity with the goal to provide more than one billion doses globally. Johnson & Johnson expects to initiate human clinical studies of its lead vaccine by September 2020 at the latest and anticipates the first batches of a vaccine could be available for emergency use in early 2021. This is again a substantially accelerated timeframe compared to the typical vaccine development process14.
Sanofi is engaged in two partnerships: one with BARDA using an existing technology designed to tackle influenza and another with Translate Bio to combine its deep vaccine expertise with Translate Bio’s mRNA platform to discover, design and manufacture several vaccine candidates15.
Pfizer has teamed with BioNTech to co-develop and distribute an mRNA vaccine, similar to Moderna’s. The partners plan to use multiple R&D sites in the US and Germany to accelerate progress of a vaccine that began clinical testing in humans at the end of April 202016.
When will a vaccine be available?
The earliest we can expect a successful vaccine candidate will be 12 to18 months, which would be a huge advance over traditional timelines. Vaccine development typically takes more than a decade with approval success rates of 10-15% as it moves from phase 1 to successful phase 3 clinical trials. One global analytics firm estimates the Moderna and Inovio studies, assuming they are successful, will still require five years before securing full regulatory approval. The same firm estimates either trial has a one in 20 chance of success17. Assuming the odds are overcome and regulatory authorities speed reviews, an initial vaccine may be produced by early to mid-2021, at the earliest.
There are good reasons to allow sufficient time to check for safety and efficacy. It's critical to ensure the vaccine does not induce a counterproductive or even dangerous immune system reaction (known as immune enhancement), and that the vaccine generates a long-term protective immune response, especially in the most vulnerable aging population18. This is particularly important given the premise that 60% of populations need to be immunised to achieve sufficient levels of herd immunity.
Assuming a successful vaccine is found, a secondary challenge will be global manufacturing and distribution. Production capacity will likely not meet the initial huge demand, distribution will take time and politics may intervene. It is also likely that more than one round of vaccination will be needed to achieve (even temporary) immunity. First recipients of the vaccine would probably be emergency medical service providers, first responders and healthcare workers, followed by the elderly in the highest risk groups19.
A further uncertainty of any COVID-19 vaccine is the duration of immunity. For comparison, there are four seasonal circulating coronaviruses that cause the mild common cold (229E, NL63, OC43 & HKU1). Our natural immunity to these is typically only short-term, although it's highly unlikely to be re-infected in the same or following season. Experience with previous SARS and MERS coronavirus epidemics suggests that immunity could last up to three years or more and recovered patients have a low risk of reinfection20.
Early evidence suggests people who recovered from COVID-19 are likely to be immune from reinfection in the short term21. To determine this more precisely, longitudinal serological studies are required to monitor patient immunity over a longer time period. Such studies are underway at the Centre for Applied Microbiology and Research at Porton Down in the UK as well as in other research centres around the world and are being strongly recommended by the WHO.
Ideally, a COVID-19 vaccine will provide protection for life, or at least many years. The WHO's current minimally acceptable and preferred profiles for COVID-19 vaccines set out a minimum protection of at least six months to 1 year with an efficacy of 50-70% on a population basis22.
Finally, we may see multiple vaccines approved. Different national regulators may have differing priorities for the development of a COVID-19 vaccine and this will guide decision making23.
Alternative immune therapies
Convalescent plasma therapy takes antibody-rich plasma from patients who have recovered COVID-19 and infuses it into individuals diagnosed with the virus. This approach dates back almost 100 years, with some evidence for benefit against rabies, hepatitis B, polio, measles, influenza, Ebola and other pathogens24.
Initial studies on 15 severe COVID-19 patients in China first suggested that convalescent plasma therapy may be a safe and promising therapeutic option25,26. On 13 April, the FDA announced an emergency investigational new drug (eIND) application process to allow physicians to treat patients with serious COVID-19 disease with convalescent plasma collected by a blood centre27.
While outcomes of these studies are optimistic, they represent a small sample and require further investigation. At this time, the use of convalescent plasma is considered an interim approach while vaccines and effective drug therapies are developed. While the concept is simple, numerous steps are involved and the process requires close cooperation between recovered donors, collection centres, treating physicians and receiving patients. Health care administrators and regulators must oversee the safety of each step28. Current estimates suggest that a single donor's plasma could be used to treat only 2-3 recipients. In addition, quantitative serologic assays are not yet widely available to identify convalescent patients with high titer neutralizing antibodies. Finally, we don't know how long this donated immunity would last, what level of protection it offers and who is most eligible to receive it.
Global efforts to develop an effective vaccine in response to the COVID-19 pandemic are unprecedented in terms of scale and speed. The earliest date one or more vaccines could be available is early to mid-2021. Despite numerous trials and significant funding, success within this timeline cannot be guaranteed, and mass production and distribution will be challenging and time consuming.
The reappearance of a novel coronavirus outbreak has been on the radar of the scientific community for some time. Leading experts agree there were missed opportunities to learn from SARS and MERS to develop a medically proven vaccine predecessor for any type of human coronavirus. Since both these corona epidemics were contained, there was less funding to find a vaccine to fight them. The good news is that coronaviruses tend to mutate less frequently than other RNA viruses, so new therapeutic regimens against other (novel) coronaviruses will increase global resilience against future pandemics.
As the world waits for vaccine trials to yield results, the pandemic will continue to be managed by a combination of non-pharmaceutical means such as social distancing, good hygiene practices and non-vaccine pharmaceutical interventions such as different antiviral and anti-inflammatory agents.
Currently, there are no reliable drug regimes to treat the infection, which is critical to save lives particularly for those with severe symptoms. It is expected that effective treatments for COVID-19 will arrive sooner than a vaccine and one or more drugs may be approved over the coming months. In our next report we will examine the pipeline of new drugs and the repurposing of existing drugs as treatment options.
Managing editor: Susan Imler, Global L&H Communications
Contributing editor: Simon Woodward, Senior Business Development Manager
Potential vaccines: Six prominent candidates in clinical trials
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