In a study among 1,077 healthy volunteers aged 18-55 years, a vaccine for COVID-19 (also known as severe acute respiratory syndrome coronavirus-2, or SARS-CoV-2) produced immune responses that look strong enough to protect humans from coronavirus infection, according to a report in The Lancet (2020; doi: https://doi.org/10.1016/S0140-6736(20)31604-4).
"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," said the study co-author, Sarah Gilbert, PhD, Professor of Vaccinology at the University of Oxford, UK.
In comments to the press, she was repeatedly asked for an estimate of a timescale for rolling out an effective vaccine. She said that her group's "Oxford vaccine" was one of many candidates under investigation internationally and that efficacy was yet to be determined by phase III investigation. She also said there were no guarantees-either about the vaccine's ability to prevent infection or about the duration of any such protection. But she was hopeful that the study's co-primary endpoint-disease prevention-would be met. The second co-primary endpoint-vaccine safety-had already been met.
Research Specifics
The randomized study included both phase I and phase II of the Oxford group's first-in-human investigation using an adenoviral-vectored vaccine. The data showed significantly-and strongly-raised immunological markers of both humoral (antigenic) and cellular (T-cell mediated) immunity that continued at least to day 56 (when the data were collected) among volunteers injected with the vaccine as compared with those receiving a control injection with the meningitis vaccine MenACWY.
A non-randomized, unblinded subgroup of 10 participants treated with a second dose of the vaccine at day 28 had even stronger immune responses. According to the researchers, the antigen and T-cell responses were potentially sufficient for the vaccine to protect humans from COVID-19 infection. The investigation was ongoing into phase III to assess the vaccine's impact on case numbers in communities around the world exposed to the infection.
The Oxford vaccine was found to have only mild or moderate adverse events among the young to middle-aged volunteers studied up to the time of reporting. Local and systemic reactions including pain, feeling feverish, chills, muscle ache, headache, and malaise were more common in the coronavirus vaccine arm of the study, but were relatively minor and were less severe in those who had paracetamol before being injected.
The phase III continuation of the study with volunteers in the UK, Brazil, and South Africa included those who were older or had comorbidities or were judged to be at higher risk for SARS-CoV-2 exposure (including health care workers). There were also plans to evaluate the vaccine in children when sufficient safety data had been gathered from adults. The aim was to assess efficacy and safety of the vaccine in diverse populations.
"As well as continuing to test our vaccine in phase III 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," said Gilbert. The Lancet report, however, drew comparisons with historical data suggesting that the antigenic and cell-mediated responses were theoretically capable of producing immunity, but with unknown duration.
The practicalities of making a vaccine available globally also guided the Oxford team. "If our vaccine is effective, it is a promising option, as these types of vaccine can be manufactured at large scale," Gilbert said. "A successful vaccine against SARS-CoV-2 could be used to prevent infection, disease, and death in the whole [global] population, with high-risk populations such as hospital workers and older adults prioritized to receive vaccination."
The researchers used an adenovirus that infects chimpanzees that had been modified to be "replication deficient" (and therefore not capable of causing disease) as a vector to carry a key immunological feature of COVID-19 into injected persons. To do this, the vector had been engineered to code for the glycoprotein spike on the surface of the SARS-CoV-2 virus. This created the candidate vaccine named ChAdOx1 nCoV-19.
A similar modified adenovirus vector-ChAdOx1 MERS-coding for Middle East respiratory syndrome (MERS) had already stimulated immune responses and was safe in humans. And it prevented MERS in non-human primates. So, its sibling vector-engineered to carry the COVID-19 spike protein harmlessly into injected persons-was a rational vaccine candidate. Since the spike protein mediates receptor binding and cell entry during infection, it was considered likely to play roles in disease transmission and in the clinical impact of the infection.
The study lead author Andrew Pollard, BSc, MBBS, PhD, Professor of Paediatric Infection and Immunity at the University of Oxford, said the new adenovirus vaccine vector was similar to a common cold virus and that the chimpanzee-infecting version had been attenuated so that it could not cause any human disease. It had also been 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 cells to produce the spike protein, and helps teach the immune system to recognize the SARS-CoV-2 virus," he noted.
Pollard said the candidate vaccine had been designed to induce both cellular and humoral immunity. "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 for an extended period." But he refrained from making any predictions about the efficacy or longevity of any protective effect.
Study Details
The initial study looked at safety and at immune marker surrogates of the vaccine's efficacy in a single-blind, randomized, controlled trial at five locations in the UK comparing it to control injection with the meningococcal conjugate vaccine.
Only the investigators knew which patients had received the investigational vaccine. The idea of using saline injections in the control group had been ruled out since patients in the control group could potentially have noticed the marked difference in reactions provoked by saline as compared with a vaccine. This could have unblinded the study and diluted the statistical power of the findings.
Trial entry was restricted to healthy adults who had never tested positive for SARS-CoV-2 infection or had COVID-19-like symptoms. (Interestingly some of the group eventually were found to have had pre-existing coronavirus antibodies. This was consistent with recent findings of substantial numbers of asymptomatic infections in the UK.)
Participants were randomly assigned to the adenoviral vector vaccine or to the meningitis control vaccine. Both the ChAdOx1 nCoV-19 (used at a dose of 5 x 1010 viral particles in the experimental arm of the study) and the MenACWY vaccine (in the control arm) were given as a single intramuscular injection.
The prophylactic use of paracetamol was introduced through a protocol amendment in two of the five study locations after the trial had begun.
Humoral responses at baseline and following vaccination were measured by a range of laboratory assays involving the SARS-CoV-2 spike protein. Three different live SARS-CoV-2 neutralization assays were also carried out on patient samples. In addition, a test of COVID-19 neutralization using a pseudovirus neutralisation assay (that avoided using the pathogenic SARS-CoV2 in the test laboratory) was performed. Cellular immune responses were measured by using the "ex-vivo interferon-[gamma] enzyme-linked immunospot assay" method to identify virus-specific T cells.
A total of 543 participants received the ChAdOx1 nCoV-19 vaccine while the remaining 534 had the meningitis vaccine. Ten of the volunteers in the investigational arm were enrolled in a non-randomized study looking at the effect of a "prime boost" of the candidate vaccine 28 days after their first injection.
Findings
Although local and systemic reactions-including pain, feeling feverish, chills, muscle ache, headache, and malaise-were more common in the coronavirus vaccine group, many of these were reduced by using prophylactic paracetamol. There were no serious adverse events related to ChAdOx1 nCoV-19. In the investigational group, T-cell responses specific to the COVID-19 spike molecular peaked on day 14 (with a median of 856 "spot-forming" cells per million peripheral blood mononuclear cells).
The safety endpoint was met since serious adverse events 28 days after vaccination had not appeared in any of the participants.
Surrogates for efficacy were found to be positive. Anti-spike antibody response (assessed by immunoglobulin G [IgG]) increased by day 28 to a median of 157 ELISA units (EU). This went even higher in the subgroup who had a second dose of the vaccine (rising to 639 EU). Neutralizing antibody responses against the SARS-CoV-2 virus were detected in 32 (91%) of 35 participants after a single dose according to the MNA80 assay. Using the alternative PRNT50 test increased to all 35 participants.
Virus neutralization was increased in subjects who had the booster dose, all of whom tested positive for neutralizing activity (nine of nine) at day 42, according to both the MNA assay and from assessment using the Marburg VN assay on day 56. There was a strong correlation of neutralizing antibody responses with the findings on antibody levels measured by ELISA.
The researchers concluded that ChAdOx1 nCoV-19 showed an acceptable safety profile and that a boost vaccination had increased antibody responses. They wrote that the results supported large-scale evaluation of this candidate vaccine in the ongoing phase III program.
Commenting on the Oxford group's findings and on Chinese data for using an adenovirus vector as a vaccine for SARS-CoV-2, Naor Bar-Zeev, PhD, Associate Professor at the International Vaccine Access Center at Johns Hopkins Bloomberg School of Public Health, said the trials had been hugely anticipated.
"The results of both studies augur well for phase III trials to assess their efficacy and safety." He regarded the use of adenovirus vectors to deliver and study the COVID-19 vaccine as "an innovative and efficient means of vaccine development in the midst of a pandemic." He said adenovirus vectored vaccines had "much potential."
But he warned that the technology was new. "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."
Peter M. Goodwin is a contributing writer.