COVID-19 vaccines November update: progress of clinical trials

A successful COVID-19 vaccine, complementing other non-pharmaceutical interventions aiming to reduce the spread of SARS-CoV-2, has the potential to eradicate the disease. Immunising the whole population, vulnerable groups or people most likely to transmit the virus is considered by many to be the most important and effective intervention. Immunisation could suppress the transmission of the virus, reduce the incidence of illness and mortality, and allow the lifting of restrictions on daily life. At present it is unknown whether there will be a successful COVID-19 vaccine and whether it will be able to provide complete protection from SARS-CoV-2 infection.

Development of COVID-19 vaccines started as soon as the sequence of SARS-CoV-2 was identified and is progressing at unprecedented speed. The completion of some clinical trials is expected by the end of 2020. The UK has pledged £250m to the Coalition for Epidemic Preparedness Innovations (CEPI) for the development of a SARS-CoV-2 vaccine and has changed regulations to allow a COVID-19 vaccine to be fast-tracked.

As of 3 November 2020, the latest World Health Organization figures show over 200 vaccines in development, 47 of which are being tested in people. New vaccines in development are often called ‘candidates’. COVID-19 vaccine candidates are developed using a variety of technologies, based on using different methods to stimulate an immune response. Information on single vaccine candidates can be found in the COVID-19 vaccine tracker developed by the Vaccine Centre at the London School of Hygiene & Tropical Medicine. COVID-19 vaccines have been widely discussed in Parliament, most recently during a public hearing at a joint Commons Science and Technology and Health and Social Care Committee inquiry Coronavirus: lessons learnt.

In this article the most advanced COVID-19 vaccine candidates (the ‘first generation’) will be described.

What can we expect from the first generation of COVID-19 vaccines?

As highlighted by the Chair of the UK Vaccine Taskforce, the first vaccine candidates to be approved are likely to be imperfect. Vaccines reducing the severity of diseases are called ‘disease-modifying’ vaccines, while those reducing the level of virus are called ‘sterilising’ vaccines. The first generation of COVID-19 vaccines will probably be disease-modifying rather than sterilising and they will probably not work in everyone. The type and duration of protection provided will also be in question. As highlighted by a recent report from the Data Evaluation and Learning for Viral Epidemics (DELVE) initiative, a vaccine providing only partial immunity will mean that higher vaccination rates are needed to control infection. Some experts warn that the first vaccines approved might make it harder for other candidates to recruit volunteers or to demonstrate their effectiveness.

Which vaccines are in the final stages of clinical trials?

To be granted approval, a vaccine candidate needs to be successful in all phases of clinical trials:

• Phase I trials involve a small group of healthy people (<100) and aim to make sure that there are no safety concerns, to see how well it stimulates an immune response and to work out an effective dose.
• Phase II trials involve several hundred people and aim to see whether the vaccine works consistently, to assess the immune response and to look for side effects.
• Phase III trials involve several thousand people under natural disease conditions. This produces enough data to identify rare side effects and to evaluate whether the vaccine produces enough immunity to prevent and/or reduce the disease.

There are currently 11 vaccine candidates being tested in large Phase III clinical trials. A recent review published in the Lancet describes them in more detail. The table below summarises Phase III trials for different candidates, indicating the expected completion date. The candidates for which the UK has secured early access are indicated with an asterisk.

There are currently 11 vaccine candidates being tested in large Phase III clinical trials. A recent review published in the Lancet describes them in more detail. The table below summarises Phase III trials for different candidates, indicating the expected completion date. The candidates for which the UK has secured early access are indicated with an asterisk.

Adapted from Poland et al. (2020) and the COVID-19 vaccine tracker (Vaccine Centre at the London School of Hygiene & Tropical Medicine). The asterisks indicate candidates for which the UK has secured early access.

Briefly, these are the latest updates for candidates in Phase III trials. Regulatory approval work and patenting are indicated when relevant:

The CanSinoBIO / Chinese Academy of Military Medical Sciences adenovirus-based candidate

Updates on clinical trials: Phase III trials are taking place in Pakistan and Russia, but data are not yet available. Phase III trials are also expected to start in Saudi Arabia.

Data about vaccine performance: Results from Phase II clinical trials were published on 15 August, showing that the vaccine triggers an antibody response.

Regulatory approval work: On 25 June it was reportedly approved for use in the Chinese military for a year.

Patenting activity: On 15 September, China granted the first COVID-19 vaccine patent to CanSinoBIO.

The Oxford University / AstraZeneca adenovirus-based vaccine candidate

Updates on clinical trials: On 6 September all trials around the world temporarily paused to review the safety data of a single event of unexplained illness (neurological symptoms resembling transverse myelitis) that occurred in the UK Phase III trial. Pausing trials is a common safety precaution during Phase III. After proving that the episode wasn’t related to the vaccine, trials in the UK resumed on 12 September. Later they also resumed in Brazil, South Africa, India and Japan. On 23 October, the US Food and Drug Administration (FDA) authorised the restart of clinical trials in the US. The UK has secured 100m doses of this vaccine candidate.

Data about vaccine performance: On 15 October, results on Phase I/II clinical trials showed the induction of both antibodies and a T-cell immune response. On 26 October, AstraZeneca reported that the candidate produces an immune response in both young and old adults. Phase III data are not published yet.

Regulatory approval work: At the beginning of October, the European Medicines Agency (EMA) started a rolling review of this vaccine candidate, evaluating the preclinical data available. This regulatory tool is intended to speed up the assessment of promising medicines or vaccines during a public health emergency. On 1 November, AstraZeneca confirmed that the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) started an accelerated review of its vaccine candidate. 

The Novavax protein-based candidate

Updates on clinical trials: On 24 September, Phase 3 trials started in the UK. The expected completion date is between January and February 2021. The UK has secured 60m doses of this vaccine candidate.

Data about vaccine performance: On 19 August, a study (not peer-reviewed) provided protection from SARS-CoV-2 infection in monkeys. On 2 September results of Phase I/II trials were published.

The Chinese Sinovac inactivated candidate (CoronaVac)

Updates on clinical trials: Phase III trials are currently ongoing in Brazil, Turkey and Indonesia. After describing it as the most promising candidate at the end of October, Brazil has authorised the import of 6 million doses of this vaccine. 

Data about vaccine performance: In September, the company announced preliminary results of Phase I/II clinical trials in the elderly and the approval of Phase I/II trials in adolescents and children.  

Regulatory approval work: On 28 August CoronaVac was approved for emergency use in China as part of a programme to vaccinate high-risk groups such as medical staff. Reportedly, in one Chinese city, essential workers and other high-risk groups can get vaccinated for US $60. 

The Russian Gamaleya Research Centre adenovirus-based candidate (Sputnik V)

Updates on clinical trials: Phase III clinical trials started at the end of September. These will involve 40,000 volunteers receiving two shots of the vaccine candidate. On 29 October, it was reported that vaccinations were temporarily suspended in some trial clinics, due to high demand and shortage of doses. The Russian Ministry of Health and the Gamaleya Centre denied that these trials had been suspended. 

Data about vaccine performance: At the beginning of September, results from Phase I/II trials were published in the Lancet. The study design triggered criticisms among several vaccine experts as they were neither-blind nor randomised. The data have since been questioned and almost 40 experts signed an open letter to the Lancet raising concerns about data duplication. 

Regulatory approval work: On 11 August, this candidate was approved for use in vulnerable groups, including medical staff and the elderly in Russia. Wider use will be allowed only after 1 January 2021.  

The Sinopharm / Wuhan Institute of Biological Products inactivated virus candidate

Updates on clinical trials: Phase III trials are currently ongoing in the United Arab Emirates (UAE), Bahrain, Jordan and Morocco.

Data about vaccine performance: Preliminary results from Phase I studies were published on 13 August.

The Sinopharm / Beijing Institute of Biological Products inactivated virus candidate

Updates on clinical trials: Phase I/II clinical trials started on 28 April and Phase III trials are currently ongoing in UAE and Argentina. 

Data about vaccine performance: Results from Phase I/II trials were published on 15 October. 

Regulatory approval work: Before completion of Phase III trials, Sinopharm announced approval for emergency use in China in July and in United Arab Emirates (UAE) on 24 September. It is unclear whether approval in UAE was granted to one or both candidates. 

The BioNTech / Fosun Pharma / Pfizer RNA-based vaccine candidate (BNT162)

Updates on clinical trials: On 12 September this team announced the expansion of their US-based Phase III trials to include up to approximately 44,000 participants. The UK has secured 30m doses of this vaccine candidate. 

Data about vaccine performance: On 12 August, results from Phase I/II study were published. On 28 August a study (not yet peer-reviewed) identified the most efficacious version of the BNT162 vaccine to be used in Phase II/III clinical trials. Mostly mild to moderate side effects were identified during the initial Phase III trials in US, Brazil and Argentina.  

Regulatory approval work: The EMA started a rolling review of this vaccine candidate on 6 October. On 30 October, it was reported that the UK MHRA had started an accelerated review of this vaccine candidate. 

The US National Institute of Allergy and Infectious Diseases (NIAID) / Moderna RNA-based candidate

Updates on clinical trials: Enrolment of participants for Phase III studies in the USA was completed on 22 October. 

Data about vaccine performance: On 14 July preliminary data for the Phase I trial were published and on 28 July data showed protection from SARS-CoV-2 infection in monkeys. On 29 September further results from Phase I studies confirmed the stimulation of an immune response in older adults.

The Janssen / Johnson & Johnson adenovirus-based vaccine candidate:

Updates on clinical trials: On 23 September, the companies announced the beginning of Phase III clinical trials. Trials stopped in the US on 12 October following a serious medical event experienced by one study participant and restarted a few days later, after no clear cause was identified. The UK has secured 30m doses of this vaccine candidate. 

Data about vaccine performance: On 30 July, data in monkeys demonstrated that this vaccine candidate requires a single dose to induce protection. All the other candidates in Phase III clinal trials require two doses. On 25 September preliminary data on Phase I/II clinical trials were published.  

Indian Council of Medical Research, the National Institute of Virology and the Indian company Bharat Biotech inactivated virus vaccine candidate

Updates on clinical trials: On 23 October the beginning of Phase III clinical trials were announced.

Data about vaccine performance: Only preclinical data from monkeys and hamsters are publicly available at the moment.

Which COVID-19 vaccines have been approved for use in people and where?

So far, six vaccine candidates (developed in China and Russia) have been approved for use in other countries before completion of Phase III trials. Data available on these candidates are limited and it is very difficult to assess whether they are safe and effective. The UK is not actively pursuing early approval of any of these candidates. Even though research for COVID-19 vaccines has been accelerated (for example, via Phase I/II combined trials), results from Phase III clinical trials are still required by the MHRA, as they demonstrate both safety and efficacy of a vaccine candidate

Companies whose candidates have been granted approval before completion of trials (where approved):

• The CanSinoBIO / Chinese Academy of Military Medical Sciences, developing an adenovirus-based candidate (China)
• The Chinese Sinopharm, developing two inactivated-virus candidates (China and UAE)
• The Chinese Sinovac, developing an inactivated-virus candidate (China)
• The Russian Gamaleya Research Centre, developing an adenovirus-based candidate (Russia)
• The Russian Vektor Institute, developing a protein-based candidate (Russia). Regulatory approval was received on 18 October and the Russian Ministry of Health said the candidate is due to enter public circulation on 1 January 2021. Post-registration Phase III clinical trials are due to begin in November.

In the next month, a third Russian vaccine could be approved in Russia before starting Phase III trials.

UK Government support for COVID-19 vaccine research and vaccine purchase agreements

The UK Government supported COVID-19 vaccine research by pledging £250m to the Coalition for Epidemic Preparedness Innovations (CEPI) for the development of a SARS-CoV-2 vaccine, and by investing £65.5m in the vaccine candidate developed by the University of Oxford and £41m in the one developed by Imperial College London. The vaccine candidate developed by the University of Oxford is one of the closest to conclude Phase III clinical trials, while the one developed by Imperial College London is still recruiting participants for Phase I/II trials (as of 5 November 2020). However, preliminary data presented at the European Parliament show promising results.

On 24 September, a small clinical trial funded by UK Research and Innovation and the National Institute for Health Research was set out to evaluate the effectiveness of the Oxford and Imperial candidates when delivered by inhalation (rather than injection into muscle). This study will monitor whether they can generate an immune response in the airways, creating a local first-line of defence against SARS-CoV-2 infection.

UK purchase agreements for early access

So far, the UK has secured early access to more than 340 million doses of six different vaccine candidates in total. Four of these (from Oxford / AstraZeneca, BioNTech / Fosun Pharma / Pfizer, Novavax and Janssen / Johnson & Johnson) are in Phase III clinical trials, while the other two are in earlier stages of development:

• The GSK/Sanofi Pasteur protein-based candidate started Phase I/II trials on 3 September. In July, the UK Government had secured 60m doses of this vaccine.
• The Valneva inactivated virus-based candidate is still in preclinical trials. The UK Government secured 60m doses of this candidate in July, with the possibility to acquire a further 40m doses if proven effective, safe and suitable.

Investing in vaccines that are based on different technologies increases the chances of having access to a successful vaccine, or to different vaccines that are better suited to specific groups (such as the elderly).