COVID-19 vaccine development – what’s the story so far?

(Published October 2020)

Work towards approval for a Covid-19 vaccine is progressing rapidly and new information is emerging every day. At the time of writing we have three very effective vaccines for Covid-19 about to be marketed and presented to the appropriate regulatory authorities to authorise emergency use.

These first Covid-19 vaccines could be approved for use in early 2021, with completed trials showing an efficacy of 95%, which is amazing for three separate vaccines. There are more than 300 Covid-19 vaccine candidates currently in development, with over 40 in clinical trials. In early October 2020, the European Medicines Agency said it was starting a rolling review to speed up the assessment of two vaccines for Covid-19, the ChAdOx1 vaccine being developed by Oxford University and AstraZeneca, and the BNT162b2 vaccine being developed by BioNTech and Pfizer. However, once a vaccine is approved, manufacturers will then need to ensure there is enough of it to deliver it, fairly, to billions of people across the world. The World Health Organization says it does not expect widespread dissemination of a Covid-19 vaccine until the middle of 2021 at the earliest. Calculations by the Coalition for Epidemic Preparedness Innovations show that, even if manufacturing capacity doubled, as planned, over the next 12 months, less than half the world’s population could be protected against Covid-19 by the end of 2022.

300 COVID-19 vaccine candidates

Of the 300 vaccines, the majority of these are at the pre-clinical phase of development, with approx. 40 in clinical trials. Only phase III trials can determine if the vaccine protects against Covid-19. Many phase III vaccine studies fail because the dose chosen does not best balance safety and efficacy, and because they are large enough to reveal evidence of relatively rare side effects that might be missed in earlier, smaller scale studies. If there is sufficient evidence to demonstrate the safety, quality and efficacy of a vaccine against Covid-19, a temporary authorisation for the supply of the vaccine could be given by the licensing authorities before the vaccine is officially licensed. Based on previous vaccine development, those at the pre-clinical stage have roughly a 7% chance of succeeding, while those that make it to clinical trials have about a 20% chance of succeeding. One way in which development of Covid-19 vaccines has been accelerated is by combining clinical research phases, so some vaccines have undergone, or are currently undergoing, phase I/II or phase II/III trials.

Phase III trials in very large groups of 40,000+ patients have shown 90-95% efficacy and a very low incidence of minor side effects, like headaches or fatigue which wear off in a day or two. This is fantastic news!

COVID-19 vaccines have already been approved for use

Two adenoviral vector vaccines have been given early or limited approval without waiting for the results of phase III trials.

Sputnik V, a combination of two adenoviruses, Ad5 and Ad26, formerly known as Gam-Covid-Vac, which is being developed by the Gamaleya Research Institute in Moscow, Russia, was approved by the Ministry of Health of the Russian Federation in August 2020. However, experts have raised considerable concerns about the vaccine’s safety and efficacy, given it has not yet entered phase III clinical trials. Another vaccine developed by the Chinese company CanSino Biologics, which is based on the adenovirus Ad5, was approved by the Chinese military in June 2020 for a year as “a specially needed drug”. In August 2020, the company announced that it plans to start phase III trials of its vaccine in Russia.

Four of the six vaccines being backed by the UK are already in phase III trials

This includes the Oxford University/AstraZeneca ChAdOx1 adenoviral vector vaccine, which carried out phase III clinical trials in South Africa, Brazil and the United States, as well as phase II/ III trials in the UK. The UK trial involves
10,000 adults and children.

Novavax’s protein adjuvant vaccine began phase III UK trials in September 2020, with 10,000 adults aged 18–84 years, with and without relevant comorbidities.

Also in September 2020, Janssen launched phase III trials of its adenoviral vector vaccine. One trial will test a single-dose regimen across three continents, involving up to 60,000 adults, with and without comorbidities. A separate phase III trial of a two-dose regimen in multiple countries will be conducted in parallel.

BioNTech and Pfizer carried out phase II/III trials of their RNA vaccine with more than 25,000 volunteers in the United States, Argentina and Brazil.

It is unlikely that one vaccine will be suitable for all sectors of the population, and booster doses may be needed. Much like influenza vaccines, it is likely that we will need different types of Covid-19 vaccines for different sectors of the population. For example, there is little evidence of the safety of RNA vaccines in children and pregnant women, whereas the protein-adjuvant platforms have long experience in children. However, it has now been shown that the three vaccines awaiting approval are equally effective in older age groups.

There are also concerns that some people may already have immunity to the vectors used in adenoviral vector vaccines, which may end up hampering, or even neutralising, the new vaccines. However, the adenoviral vectors being used in vaccines have been designed to overcome this problem.

In addition, it is not yet known how long the vaccine-induced protection may last in humans, and it remains possible that booster vaccinations will be required to sustain protection against Covid-19. The need for boosters is likely to influence the choice of vaccine platform used since immunity induced by a first dose of viral vector vaccine may make them unsuitable for a booster dose, meaning that a combination of different vaccines is required.

The World Health Organization gives a target efficacy for SARS-CoV-2 vaccines of at least 50% (preferably 70%), including in older people; flu vaccinations, for example, are only 40–60% effective. Initial results for the first three vaccines are showing an efficacy of approx. 95%, which means that they could be some of the most effective vaccines ever.

The effectiveness of a vaccine can be influenced by how it gets into the body. All of the first-wave vaccines that are now in clinical trials have to be injected into muscle. A spray, similar to that used to deliver asthma medicines, might work better, since the coronavirus invades our bodies through the airway. This approach is currently being investigated in small trials to assess the safety and effectiveness of Oxford University’s adenoviral vector vaccine and Imperial College London’s RNA vaccine. Ultimately, rigorous testing is required across all populations to make the careful decisions needed for vaccine development and eventual delivery.

Four of the six vaccines in the UK portfolio require two doses, several weeks apart, with single and two-dose regimens being tested in trials of the other two vaccines. The need for a second dose may further complicate delivery of mass vaccination programmes.

Cold storage may be a challenge as some vaccines need to be stored at -80°C

Furthermore, there are some concerns that, depending on the Covid-19 vaccines that make it through to approval, there may be challenges associated with shipping and storage of the vaccine. RNA vaccines will need to be shipped on dry ice and stored in ultra-cold freezers. For example, mRNA is naturally unstable and needs to be stored frozen at below -20°C, and in some cases as cold as -80°C. This will complicate the global shipping and clinical use of RNA vaccines. Imperial College London, which is developing an RNA vaccine, has said that although, initially, its vaccine will be a frozen product, it will look to rapidly transition to a 2–8°C presentation, with a freeze-dried product as a longer-term option. Some vaccines, including the adenoviral vector vaccines, adjuvanted protein vaccines and inactivated whole virus vaccines, are expected to be stable at 2–8°C, so storage for those will be the same as for influenza vaccines.

Many countries are taking steps to help bolster vaccine manufacturing capacity. In the UK, in May 2020, the Government announced that it was investing up to £93m to open the UK’s first dedicated Vaccine Manufacturing and Innovation Centre (VMIC), 12 months early, in summer 2021. While the VMIC is being built, a rapid deployment facility has been established with a further investment of £38m, to begin manufacturing in 2020. Also the UK has made several other deals, including one with the Indian pharmaceutical company Wockhardt, in which the company has agreed to carry out the “fill and finish” stage of the manufacturing process, whereby the vaccine is dispensed into vials ready for distribution. Wockhardt has a manufacturing capacity of 400 million doses.

In addition, several of the main vaccine developers have made deals with manufacturers in different countries to secure sufficient capacity. For example, AstraZeneca, which has partnered with Oxford University on its vaccine, has reportedly made deals with more than 20 contract manufacturing organisations to hit its goal of delivering 2 billion doses by the end of 2021.

Herd Immunity

At least 60% of the population would have to be immune to achieve herd immunity, which could take years. Herd immunity describes the process by which at-risk individuals are protected from infection because they are surrounded by immune individuals, therefore minimising spread of the virus. Public health strategies to control Covid-19 generally fall into two categories: ‘mitigation’, which aims to achieve herd immunity by allowing the virus to spread through the population while mitigating disease burden so as not to overwhelm the health service, and ‘suppression’, which aims to drastically reduce SARS-CoV-2 transmission rates and halt endogenous transmission in the target population. Herd immunity becomes harder to achieve when vaccine-induced or natural immunity is partial or only for a limited period, or when logistical or other constraints limit roll-out or uptake of a vaccine.

However, once we have a mass vaccination program of the population, we should get back to normal, and we can look forward with great hope for 2021. In the meantime minimising the spread of Covid-19 by practising hand hygiene, social distancing and wearing face masks is the only way we have to reduce the number of people dying of the infection.

Adapted and updated from an article in the Pharmaceutical Journal 8 October 2020