When will a coronavirus vaccine be ready?

Human trials began in April — but even if they go well, many obstacles remain before global vaccination is possible.

Even the most effective and strict containment strategies have the spread of the respiratory disease COVID-19 only slowed — which is very valuable. When the World Health Organization (WHO) finally declared an outbreak followed by a pandemic, all eyes turned to the possibility of a vaccine, because a protective vaccine can most effectively prevent people from becoming ill.

Approximately 100 companies and academic institutions are racing to create such a vaccine, and at least three have candidate vaccines that they are testing in humans. The first of these — produced by the Boston-based biotechnology company Moderna — is the RNA vaccine called mRNA-1273 that began human trials in April.

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This unprecedented speed is largely the result of China's efforts involving the genetic material of Sars-CoV-2, which causes Covid-19, through sequencing. China shared this sequence in early January, allowing research groups around the world to grow the live virus and investigate how it invades human cells and makes people ill.

But there is another reason why vaccine studies began so quickly. Although nobody had predicted that the next infectious disease to threaten the world would be caused by a coronavirus — flu (the disease caused by the influenza virus) is generally considered the greatest pandemic risk — vaccine experts had experience working on “prototype” pathogens.

Coronaviruses had recently caused two other outbreaks — severe acute respiratory syndrome (SARS) in China in 2002-04 and Middle East respiratory syndrome (MERS), which began in Saudi Arabia in 2012. In both cases, work began on vaccines that were subsequently developed, but was shelved when the outbreaks were found. One company, Maryland-based Novavax, has now remade these vaccines for Sars-CoV-2 and said it has several candidates ready to enter human trials this spring. Meanwhile, Moderna is built on earlier work on the MERS virus carried out at the National National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, United States.

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How do the novel coronavirus vaccines work?

The novel coronavirus shares 80% to 90% of its genetic material with the virus that causes SARS — hence its name Sars-CoV-2. Both consist of a strand of ribonucleic acid (RNA) inside a spherical protein capsule covered in spikes. The spikes lock onto receptors on the surface of cells lining the human lung — the same type of receptor in both cases — allowing the virus to enter the cell. Once inside, it hijacks the cell's reproductive machinery to produce more copies of itself before breaking away from the cell again and killing the normal cell in the process.

All vaccines work on the same basic principle. They present some or all of the pathogen to a person's immune system, usually by injection and at a low dose, to encourage the system to produce antibodies against the pathogen. Antibodies are a kind of immune memory that, once established, can be rapidly reactivated if the person is exposed to the virus in its natural form.

Traditionally, vaccination is carried out using live, weakened forms of the virus, or some or all of the virus inactivated by heat or chemicals. These methods have disadvantages. The live form may continue to develop in the host, for example potentially regaining some of its virulence (ability to cause disease) and making the recipient ill, while higher or repeated doses of inactivated virus are required to achieve the necessary degree of protection.

Another new strategy — such as that used by Novavax — creates a “recombinant” vaccine. This involves isolating the genetic code for the protein spike on the surface of Sars-CoV-2, the part of the virus most likely to provoke an immune reaction in humans, and inserting it into a bacterial or yeast genome so it can be produced in large quantities. A newer approach does not deal with proteins and creates vaccines from the virus's genetic material itself. This is the case for Moderna and another Boston company, CureVac, both of which use messenger RNA (mRNA) to create COVID-19 vaccines.

An important prerequisite for regulatory approval, human clinical trials usually take place in 3 stages: phase-I, phase-II and phase-III.

Phase-I involves a few dozen healthy volunteers, and the vaccine is tested to monitor safety and adverse effects. Phase-II involves hundreds of people, usually in a part of the world affected by the disease, and looks at how effective the vaccine is, while phase-III does the same in several thousand people.

However, there is a high level of attrition as experimental vaccines move through these stages. Bruce Gellin, who runs the global immunisation programme for the Washington DC-based nonprofit Sabin Vaccine Institute and collaborates with Cepi on a COVID-19 vaccine, says: "Not all the horses that leave the starting gate will finish the race". To understand this better, let us look at the graph below: only about 10% of drugs found successful in phase-I also succeed in phase-III and receive approval. The vaccines currently being tested for COVID-19 are at phase-I at most.

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So why is this? Vaccine candidates are either unsafe, ineffective, or both. Screening for suitable doses is important, so clinical trials cannot be skipped or rushed. Regulators and approval bodies can accelerate approval if they have previously approved similar products. The annual flu vaccine is the product of a well-honed assembly line in which only one or a few modules need to be updated each year. In contrast, SARS-CoV-2 is a new pathogen in humans, and many of the technologies used to make the vaccines are also relatively untested. For example, no vaccine made from genetic material (RNA or DNA) has been approved to date. COVID-19 vaccine candidates therefore need to be treated as entirely new vaccines, and as a result: "Although there is considerable motivation and a need to do things as quickly as possible, it is really important not to skip important processes."

One example is a vaccine produced in the 1960s against respiratory syncytial virus (RSV), a common virus that causes cold symptoms in children. In clinical studies, this vaccine was found to worsen disease symptoms in babies who went on to contract the virus. A similar effect was observed in animals given an early experimental SARS vaccine. The vaccine was later modified to eliminate this problem, but now that it is being redesigned for Sars-CoV-2, it will need particularly stringent safety testing to eliminate the risk of enhanced disease.

For these reasons, it can take up to 10 years for a vaccine candidate to pass all safety and efficacy tests. Nevertheless, at a meeting at the White House on 2 March — possibly thinking of the United States election in November — President Trump gave an impossible approval date. Annelies Wilder-Smith, a professor of infectious diseases at the London School of Hygiene and Tropical Medicine, says: "Like most vaccine experts, I do not think this vaccine will be ready before 18 months". It is assumed that this would already be very fast and would be the best estimate if there are no setbacks.

Meanwhile, there is another potential problem. As soon as a vaccine is approved, it will be needed in large quantities, and many of the COVID-19 vaccine organisations do not have the necessary manufacturing capacity. Vaccine development is already risky from a business perspective, because very few candidates get anywhere near the clinic. Manufacturing facilities tend to be tailored to specific vaccines, and scaling them up when you do not yet know whether your product will succeed is not commercially feasible. Cepi and similar organisations exist to cover some of the risks and encourage companies to develop much-needed vaccines. Cepi plans to invest in developing a COCID-19 vaccine and increasing manufacturing capacity in parallel, and in early March issued a call for $2 billion to do this.

If a new COVID-19 vaccine is approved, is everything settled?

Once a COVID-19 vaccine is approved, other challenges will emerge. Jonathan Quick, a global health expert at Duke University in North Carolina and author of The End, says: "Obtaining a vaccine proven safe and effective in humans takes us about one-third of the way towards what is needed for a global vaccination programme", and continues: "The biology of the virus and vaccine technology may be limiting factors, but politics and economics are more likely to be barriers to immunisation."

The problem is ensuring that the vaccine reaches everyone who needs it. This is a problem even within countries, and some have drawn up guidelines. For example, in a flu pandemic scenario, the United Kingdom will prioritise vaccination and health and social care workers, as well as those at the highest medical risk, including children and pregnant women, along with the aim of keeping overall illness and death rates low. In a pandemic, however, countries also have to compete with one another for medicines.

Because pandemics tend to harm countries with the most vulnerable and underfunded healthcare systems most, there is an inherent imbalance between need and purchasing power when it comes to vaccines. During the 2009 H1N1 flu pandemic, for example, vaccine supplies were snapped up by countries that could afford them, leaving poorer countries without. But you can imagine a scenario in which India, a major vaccine supplier to the developing world, has not unreasonably decided to use its vaccine production to protect its own vast population of 1.3 billion before exporting it.

Outside pandemics, WHO brings governments, charities and vaccine manufacturers together to agree on an equitable global distribution strategy, and organisations such as the vaccine alliance Gavi have developed innovative funding mechanisms to bring money into markets to supply poor countries. However, every pandemic is different and no country is bound by any arrangement proposed by WHO. As Gavi CEO Seth Berkley points out: "The question is, what will happen in a situation where national emergencies continue?"

Conclusion

The COVID-19 vaccine is being discussed intensively, but it will take some time before we see how it plays out. Biotechnology companies will probably see the outbreak peak and decline before they find and obtain approval for a vaccine. If a vaccine is found and the novel coronavirus becomes endemic or circulates for many years — like flu — it could save many lives. Until then, however, our best hope is to contain the disease as much as possible. Reduce social distance, wash hands and get tested in high-risk situations.

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