On July 20, 2020, The Lancet published two papers on COVID-19 vaccine candidate trials. The first discussed the results of a phase 1/2, single-blind, randomised controlled trial of the University of Oxford’s vaccine candidate, whilst the second described a phase 2, randomised, double-blind, placebo-controlled trial of China’s COVID-19 vaccine candidate. Researchers found both vaccines to be safe and induce immunity against SARS-CoV-2.

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The researchers noted that SARS-CoV-2 which was declared a pandemic on March 11, 2020, by WHO infected more than 14 million people globally with more than 5,97,000 deaths by July 19,2020. “The pandemic has placed substantial pressures on health systems delivering care for patients with COVID-19 and caused disruption of non-COVID-19 health-care provision, in addition to negative effects on the global economy. Further health consequences are anticipated," they added.

No vaccines have been approved for prevention of COVID-19. According to WHO, currently more than 137 candidate vaccines are undergoing preclinical development and 23 are in early clinical development.

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Oxford vaccine candidate

UK’s vaccine against SARS-CoV-2 is safe and induces an immune reaction, according to preliminary results.

A press release from The Lancet summarised the results of the Phase1/2 trial of the Oxford vaccine candidate thus (verbatim):

1. A phase 1/2 trial involving 1,077 healthy adults found that the vaccine induced strong antibody and T cell immune responses up to day 56 of the ongoing trial. These responses may be even greater after a second dose, according to a sub-group study of 10 participants.
2. Compared to the control group (given a meningitis vaccine), the SARS-CoV-2 vaccine caused minor side effects more frequently, but some of these could be reduced by taking paracetamol. There were no serious adverse events from the vaccine.
3. Based on their results, the authors say that further clinical studies, including in older adults, should be done with this vaccine. The current results focus on the immune response measured in the laboratory, and further testing is needed to confirm whether the vaccine effectively protects against infection.

“The early stage trial finds that the vaccine is safe, causes few side effects, and induces strong immune responses in both parts of the immune system – provoking a T cell response within 14 days of vaccination (ie, a cellular immune response, it could find and attack cells infected with the virus), and an antibody response within 28 days (ie, humoral immune response, it could find and attack the virus when it was circulating in the blood or lymphatic system),” the release clarified.

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An ideal vaccine against SARS-CoV-2

• It should be effective after one or two vaccinations
• It should work on the target populations including older adults and those with other health conditions
• It should confer protection for a minimum of six months
• It should reduce onward transmission of the virus to contacts

While conceding that the current trial is too preliminary to confirm whether the new vaccine meets these requirements, the press release revealed that phase 2 (in the UK only) and phase 3 trials will confirm whether it effectively protects against SARS-CoV-2 infection happening in the UK, Brazil and South Africa.

The lead author Professor Andrew Pollard, University of Oxford, UK, explained:

“The new vaccine is a chimpanzee adenovirus viral vector (ChAdOx1) vaccine that expresses the SARS-CoV-2 spike protein. It uses a common cold virus (adenovirus) that infects chimpanzees, which has been weakened so that it can’t cause any disease in humans, and is genetically modified to code for the spike protein of the human SARS-CoV-2 virus. This means that when the adenovirus enters vaccinated people’s cells it also delivers the spike protein genetic code. This causes these people’s cells to produce the spike protein, and helps teach the immune system to recognise the SARS-CoV-2 virus.”

The immune system has two ways of finding and attacking pathogens – antibody and T cell responses. Researchers intended this vaccine to induce both, so it can attack the virus when it’s circulating in the body, as well as attacking infected cells. They hope that the immune system will remember the virus, so that their vaccine will protect people for an extended period. “However, we need more research before we can confirm the vaccine effectively protects against SARS-CoV-2 infection, and for how long any protection lasts,” Professor Pollard added.

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The trial

The new trial included 1,077 healthy adults aged 18-55 years with no history of COVID-19; it took place in five UK hospitals between 23 April and 21 May 2020. The data included in the paper covered the first 56 days of the trial and is ongoing.

In the trial, the participants either received the new COVID-19 vaccine (543 people) or the meningococcal conjugate vaccine (534 people). 113 participants (56 given the COVID vaccine, and 57 in the control group) were also asked to take paracetamol before and for 24 hours after their vaccination to help reduce vaccine-associated reactions (as the COVID-19 vaccine was given in a high dose to help induce a strong immune response).

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Results

The vaccine was found to have an acceptable safety profile and there were no serious adverse events. Fatigue and headache were the most commonly reported reactions (around 70% [340/487] of all participants given the COVID-19 vaccine only reported fatigue, and 68% [331/487] reported headache, compared with around 48% [227/477] and 41% [195/477], respectively, of participants in the control group without paracetamol). Other common side effects included pain at the injection site, muscle ache, malaise, chills, feeling feverish, and high temperature.

Participants taking paracetamol around their vaccination had reduced pain, chills, feeling feverish, muscle ache, headache, and malaise in the two days following vaccination. In addition, in the 10 people who received the extra dose of the COVID-19 vaccine, side effects were less common after the second dose.

Researchers detected neutralising antibody responses against SARS-CoV-2, 28 days after vaccination, in 32 of 35 participants (91%), and in 35 of 35 participants (100%) who received a single dose of the COVID-19 vaccine. These responses were present in all participants who had a booster dose of the vaccine. The authors found that taking paracetamol did not affect immunogenicity of the COVID-19 vaccine.

Co-author, Professor Sarah Gilbert, University of Oxford, UK, stated that there is still much work to be done before we can confirm if our vaccine will help manage the COVID-19 pandemic, but these early results hold promise.

Prof. Gilbert clarified:

“As well as continuing to test our vaccine in phase 3 trials, we need to learn more about the virus – for example, we still do not know how strong an immune response we need to provoke to effectively protect against SARS-CoV-2 infection. If our vaccine is effective, it is a promising option as these types of vaccine can be manufactured at large scale. A successful vaccine against SARS-CoV-2 could be used to prevent infection, disease and death in the whole population, with high risk populations such as hospital workers and older adults prioritised to receive vaccination.”

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Limitations of the study

The authors admitted that there are some limitations, including that more research is needed to confirm their findings in different groups of people – including older age groups, those with other health conditions, and in ethnically and geographically diverse populations.

They revealed that these groups are being recruited in their ongoing phase 2 and 3 trials of the vaccine in the UK, Brazil and South Africa. In the current trial, 91% (979/1,077) of participants were white and the average age of participants was 35 years. The researchers will follow up the participants recruited in this study for at least one year to continue to study the vaccine’s safety and the immune response it provokes.

Dr. Doug Brown, Chief Executive of the British Society for Immunology noted that we are still in the early days of understanding what constitutes an effective long-term immune response against SARS-CoV-2.

He cautioned: “This paper shows that the Oxford vaccine elicited both neutralising antibodies and T-cell immune response against SARS-CoV-2 in the majority of patients after a single dose – this is a good first sign but we still have yet to understand whether these immune responses will have an effect if those individuals encounter the SARS-CoV-2 virus in the future.”

He asserted that the researchers working on this vaccine should be applauded for the monumental effort they have put in to move the science forward at such a fast rate. “In the quest to find both vaccines and therapeutics against this novel coronavirus, we need to make sure that we continue to support our research community to maximise our knowledge of this disease.” he pleaded.

Prof. Fiona Watt, Executive Chair of the Medical Research Council, which helped to fund the trial, said:

“It is truly remarkable how fast this vaccine has progressed, with our support, through early clinical trials, and it is very encouraging that it shows no safety concerns and evokes strong immune responses. There is a lot that we don’t yet know about immunity to the virus that causes Covid-19. However, it seems that both antibody and T cell immunity are important, and this vaccine triggers both responses. The much anticipated next milestone will be the results of the larger trials that are happening now to find out if the vaccine will protect people from the virus. The UK’s long-term investment in leading vaccine research enabled Professor Gilbert’s team to develop a vaccine to tackle a previous coronavirus outbreak, MERS, helping them to be one of the first in the world to start human trials for the COVID-19 vaccine. Many congratulations to all involved.”

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The Chinese Vaccine

Chinese phase 2 trial finds vaccine is safe and induces an immune response

Researchers carrying out a phase 2 trial of an Ad5 vectored COVID-19 vaccine candidate, in China, have found that the vaccine is safe and induces an immune response, according to new research published in The Lancet (July 20, 2020). They confirmed that Phase 3 trials are needed to confirm whether the vaccine candidate effectively protects against SARS-CoV-2 infection.

The objective of the randomised phase 2 trial was to evaluate the safety and immunogenicity of the vaccine candidate and follows a phase 1 trial published in May 2020. The results provide data from a wider group of participants than their phase 1 trial, including a small sub-group of participants aged over 55 years and older, and will inform phase 3 trials of the vaccine. However, the authors cautioned that no participants were exposed to SARS-CoV-2 virus after vaccination, so it is not possible for this study to determine whether the vaccine candidate effectively protects against SARS-CoV-2 infection.

The vaccine in this trial uses a weakened human common cold virus (adenovirus, which infects human cells readily but is incapable of causing disease) to deliver genetic material that codes for the SARS-CoV-2 spike protein to the cells. These cells then produce the spike protein, and travel to the lymph nodes where the immune system creates antibodies that will recognize that spike protein and fight off the coronavirus.

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The trial

508 participants took part in the trial. Of these, 253 received a high dose of the vaccine, 129 received a low dose and 126 received placebo. Approximately two thirds of participants (309; 61%) were aged between 18-44 years, just over a quarter (134; 26%) were aged 45-54 years, and 13% (65) were 55 years or older.

Researchers monitored the participants for immediate adverse reactions for 30 minutes after injection and were followed for any injection-site or systemic adverse reactions within 14- and 28-days post-vaccination. The researchers documented serious adverse events reported by participants during the whole study period. They took blood samples from participants immediately before the vaccination and 14 and 28 days post-vaccination to measure antibody responses.

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Results

The proportions of participants who had any adverse reactions such as fever, fatigue and injection-site pain were significantly higher in vaccine recipients than those in placebo recipients (72% [183/253] in the high dose group, 74% [96/129] in the low dose group, and 37% [46/126] in the placebo group). However, most adverse reactions were mild or moderate. Within 28 days, 24 (9%) participants in the high dose group had severe (grade 3) adverse reactions, which were significantly higher than in those receiving the low dose or placebo (one (1%) participant in the low dose group, and 2 people (2%) in the placebo group). The most common severe reaction was fever.

Professor Wei Chen, Beijing Institute of Biotechnology, China, stated that since elderly individuals face a high risk of serious illness and even death associated with COVID-19 infection, they are an important target population for a COVID-19 vaccine. They may need an additional dose in order to induce a stronger immune response but further research is underway to evaluate this.

Limitations of the study

The authors highlighted that they conducted the trial in Wuhan, China, and the baseline immunity is representative of Chinese adults at that time, but other countries may have different rates of immunity which should be considered. Additionally, the trial only followed participants for 28 days and no data about the durability of the vaccine-induced immunity is available from this study.

They mentioned, “Importantly, no participants were exposed to SARS-CoV-2 virus after vaccination, so it is not possible for this study to determine the efficacy of the candidate vaccine or any immunological risk associated with antibody induced by vaccination when having a virus exposure”.

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What do experts have to say about the vaccine candidates?

In a press release from Science Media Centre, Prof. Danny Altmann, British Society for Immunology spokesperson and Professor of Immunology at Imperial College London, stated that both reports, from Oxford and from Beijing/Wuhan, document sizeable volunteer cohorts given an experimental vaccine whereby the SARS-CoV-2 spike antigen is expressed in a construct derived from a modified adenovirus.

He noted that there are some similarities:

“Both studies show a good safety profile. If the starting premise is that effective vaccines need to be able to safely induce decent levels of neutralising antibodies blocking virus entry and to induce a good frequency of antiviral T cells, each of these studies show that these goals are achievable.”

He elaborated the differences:

“The Beijing approach is based on the backbone of a conventional human, common-cold virus to which some people have pre-existing antibodies and they therefore make a lower response in some people to the vaccine because people have pre-existing antibodies to their vector, so may clear it before it has a chance to work properly.”

“The Oxford approach overcomes this by deriving a chimp adenovirus platform to which humans have not made prior antibodies. While both vaccines raise a T cell response, the frequency of cells stimulated to respond by the Oxford vaccine look substantially higher, which would almost certainly be advantageous. On the other hand, the Oxford approach is based on two injections (“prime-boost”), which would add considerably to logistic demands. Next steps, as the teams confirm, will be to establish durability and protective efficacy of these responses, including in people of different age-groups.” he clarified.

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Prof. Jonathan Ball, Professor of Molecular Virology, University of Nottingham, stated that the results of the Oxford chimp adenovirus vaccine candidate show that the vaccine is able to generate antibodies and T cells in humans and these persisted for several weeks.

“Whilst encouraging there is still a long way to go before we can herald the arrival of a successful coronavirus vaccine,” he added. He also cautioned- “It is unclear whether the levels of immunity can protect against infection – that’s what the larger ongoing phase 3 trials are designed to test. Nor do we know if this vaccine can protect those most vulnerable to severe COVID-19 diseases.”

He felt that whilst the vaccine trialled in China used a different adenovirus to deliver the coronavirus protein, the fact that the immunity seen in the elderly included in the study was much lower than that observed in younger people is telling. “At the very least a successful vaccine will either have to protect the elderly from serious disease or prevent less vulnerable people from becoming infected and spreading the virus. And at the moment, we don’t know which if any of the many vaccine candidates being trialled will achieve that.” he cautioned.

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In the press release from Science Media Centre, Alex Harris, Head of Global Policy & Advocacy at Wellcome noted that this is just one crucial step but it’s very encouraging, and builds on the incredible global research effort during this crisis. “To see promising results from several candidates in months is remarkable, but we must also be prepared for some candidates to fail in the later stages and be realistic about timeframes for manufacturing and rollout,” he cautioned. “Meeting the global demand of billions of doses will require more than one vaccine; it is in the best interest of all governments to work openly and collaboratively, pooling expertise and funding to access the broadest pool of promising candidates,” he pleaded.

On July 21, 2020 the cases worldwide were 14,855,107 with 613,248 deaths. Every day over 5000 precious lives are lost now. “COVID-19 is a global challenge: no one is safe until everyone is safe. The fastest, most effective way to beat the disease and end this pandemic is by securing vaccines, tests and treatments for those who are at most risk everywhere,” Alex Haris reminded every one.

It is very heartening to note that there is some light at the end of the tunnel.

Disclaimer- The views and opinions expressed in this article are those of the author's and do not necessarily reflect the official policy or position of M3 India.

Dr. K S Parthasarathy is a freelance science journalist and a former Secretary of the Atomic Energy Regulatory Board. He is available at ksparth@yahoo.co.uk