Media releaseFrom: The Lancet
The Lancet: UK’s vaccine against SARS-CoV-2 is safe and induces an immune reaction, according to preliminary results
Promising early stage results from a phase 1/2 clinical trial of the UK’s vaccine candidate against SARS-CoV-2 (the virus that causes COVID-19) are published today in The Lancet.
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 with 28 days (ie, humoral immune response, it could find and attack the virus when it was circulating in the blood or lymphatic system).
An ideal vaccine against SARS-CoV-2 should be effective after one or two vaccinations, work in target populations including older adults and those with other health conditions, confer protection for a minimum of six months, and reduce onward transmission of the virus to contacts. The current trial is too preliminary to confirm whether the new vaccine meets these requirements, but phase 2 (in the UK only) and phase 3 trials to confirm whether it effectively protects against SARS-CoV-2 infection are happening in the UK, Brazil and South Africa.
Explaining how the vaccine works, study lead author Professor Andrew Pollard, University of Oxford, UK, says: “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.” 
He continues: “The immune system has two ways of finding and attacking pathogens – antibody and T cell responses. This vaccine is intended to induce both, so it can attack the virus when it’s circulating in the body, as well as attacking infected cells. We hope this means the immune system will remember the virus, so that our 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.” 
The new trial included 1,077 healthy adults aged 18-55 years with no history of COVID-19, and 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.
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).
All participants gave additional blood samples and underwent clinical assessments to determine if the vaccine was safe and whether it provoked an immune response. Participants were also asked to record any adverse events throughout the trial.
The participants were split into four groups. Group 1 (88 people) had additional safety monitoring to form the phase 1 part of the trial, and had antibody and T cell responses assessed. Group 2 (412 people) had extra blood taken to assess for antibody and T cell responses, and group 4 (567 people) had serum taken to assess for antibody response only. In groups 1, 2 and 4 half the participants received the COVID-19 vaccine and half received the control vaccine. Group 3 (10 people) received only the COVID-19 vaccine, and were given an extra dose of vaccine 28 days after the first dose to determine safety and whether this boosted antibody and T cell responses.
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.
The authors found that there were strong antibody and T cell responses from the vaccine. T cell responses targeting the SARS-CoV-2 spike protein were markedly increased (in the 43 participants studied), peaking 14 days after vaccination (median 856 spot-forming cells per million peripheral blood mononuclear cells), with this level declining slightly by day 56 of the trial (to median 424 spot-forming cells per million peripheral blood mononuclear cells) . The T cell response did not increase with a second dose of the vaccine, which is consistent with other vaccines of this kind.
Antibody responses peaked by day 28 (median 157 ELISA units – studied in 127 participants) and remained high until the measurement at day 56 in the trial (median 119 ELISA units – studied in 43 participants) for those given a single vaccine. This response was boosted by a second dose (median 639 ELISA units at day 56 in these 10 participants).
28 days after vaccination, neutralising antibody responses against SARS-CoV-2 were detected in 32 of 35 participants (91%) (when measured in MNA80 neutralisation assay), and in 35 of 35 participants (100% - when measured in PRNT50 neutralisation assay) 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 (nine of nine participants in MNA80 assay at day 42, and ten of ten in Marburg VN assay on day 56).
The authors found that taking paracetamol did not affect immunogenicity of the COVID-19 vaccine.
Co-author, Professor Sarah Gilbert, University of Oxford, UK, says: “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. 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.” 
The authors note 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. The authors note 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.
They also note that a small number of participants had detectable neutralizing antibodies and T cell responses against SARS-CoV-2 spike protein before vaccination, likely to be due to past asymptomatic infection as potential participants with recent COVID-19-like symptoms or with a history of positive PCR test for SARS-CoV-2 were excluded from the study.
The authors say the participants recruited in this study will be followed-up for at least one year to continue to study the vaccine’s safety and the immune response it provokes.
Writing in a linked Comment discussing both Articles, lead author Assistant Professor Naor Bar-Zeev (who was not involved in the two studies), International Vaccine Access Center, Johns Hopkins Bloomberg School of Public Health, USA, says: “These trial reports are hugely anticipated. The results of both studies augur well for phase 3 trials, where the vaccines must be tested on much larger populations of participants to assess their efficacy and safety… Both trials used adenovirus vectors to deliver and study the COVID-19 vaccine, an innovative and efficient means of vaccine development in the midst of a pandemic. Capable of generating humoral, cellular, and innate responses, adenovirus vectored vaccines have much potential.”
However, he warns of the preliminary nature of the two vaccine candidates. He continues: “The platform [adenovirus vectored vaccines] only achieved European Commission regulatory licensure on July 1, 2020, with the Ebola vaccine. Much remains unknown about these and other COVID-19 vaccines in development, including longevity of response and immunogenicity in older adults or other specific groups, such as those with comorbidities who are often excluded from clinical trials, or ethnic or racial groups more severely affected by COVID-19.”
The Lancet: Chinese phase 2 trial finds vaccine is safe and induces an immune response
A phase 2 trial of an Ad5 vectored COVID-19 vaccine candidate, conducted in China, has found that the vaccine is safe and induces an immune response, according to new research published in The Lancet.
The randomised trial sought 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 note that it is important to stress 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.
Professor Feng-Cai Zhu, Jiangsu Provincial Center for Disease Control and Prevention, China, says: “The phase 2 trial adds further evidence on safety and immunogenicity in a large population than the phase 1 trial. This is an important step in evaluating this early-stage experimental vaccine and phase 3 trials are now underway.” 
Currently, there are about 250 candidate vaccines against SARS-CoV-2 in development worldwide, including mRNA vaccines, replicating or non-replicating viral vectored vaccines, DNA vaccines, autologous dendritic cell-based vaccine and inactive virus vaccines. At least 17 of them are currently under evaluation in clinical trials.
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.
508 participants took part in the trial of the new vaccine. Of these, 253 received a high dose of the vaccine (at 1×1011 viral particles/1.0mL), 129 received a low dose (at 5×1010 viral particles/1.0mL) and 126 received placebo. Approximately two thirds of participants (309; 61%) were aged in 18-44 years, a quarter (134; 26%) were aged 45-54 years, and 13% (65) were 55 years or older.
Participants were monitored 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. Serious adverse events reported by participants during the whole study period were documented. Blood samples were taken from participants immediately before the vaccination and 14- and 28-days post-vaccination to measure antibody responses.
The trial found that 95% (241/253) of participants in the high dose group and 91% (118/129) of the recipients in the low dose group showed either T cell or antibody immune responses at day 28 post-vaccination.
The vaccine induced a neutralising antibody response in 59% (148/253) and 47% (61/129) of participants, and binding antibody response in 96% (244/253) and 97% (125/129) of participants, in the high and low dose groups, respectively, by day 28. The participants in the placebo group showed no antibody increase from baseline.
Both doses of the vaccine induced significant neutralising antibody responses to live SARS-CoV-2, with geometric mean titres of 19.5, and 18.3 in participants receiving the high and low dose, respectively. The binding antibody response peaked at 656.5 ELISA units and 571 ELISA units for the high and low dose of the vaccine, respectively.
T cell responses were also found in 90% (227/253) and 88% (113/129) of participants receiving the vaccine at high and low dose, respectively. A median of 11 spot-forming cells and 10 spot-forming cells per 1 × 10⁵ peripheral blood mononuclear cells in participants in the high dose and low dose groups, respectively, were observed at day 28.
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, 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 was 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.
The authors note that pre-existing immunity to the human adenovirus which was used as the vector (ie, the Ad5 vector) for this vaccine and increasing age could partially hamper the specific immune responses to vaccination, particularly for the antibody responses. Among the 508 participants, 266 (52%) participants showed a high pre-existing immunity to Ad5 vector, while 242 (48%) had low pre-existing immunity to Ad5 vector. Those with a higher pre-existing anti-Ad5 immunity showed an inferior immune response (the binding and neutralising antibody levels were around two times larger in people with low pre-existing anti-Ad5 immunity, compared to those with high pre-existing immunity). Compared with the younger population, older participants generally had significantly lower immune responses and higher tolerability to the Ad5 vectored COVID-19 vaccine.
Professor Wei Chen, Beijing Institute of Biotechnology, China, says: “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. It is possible that an additional dose may be needed in order to induce a stronger immune response in the elderly population, but further research is underway to evaluate this.” 
The authors note that the trial was conducted 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. 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.