番茄社区

The chimpanzee adenovirus viral vector vaccine (ChAdOx1) against the COVID-19 coronavirus, developed at Oxford University in England, was safe and produced an immune response in healthy adult volunteers, interim data from a phase I/II trial showed.

Phase II data on a competing vaccine from China, also using an adenovirus vector to deliver a gene encoding SARS-CoV-2 antigen, also indicated the product could be effective.

These data, published simultaneously in The Lancet on Monday, along with phase I results on Moderna's mRNA vaccine published last week, all suggest that a vaccine -- and perhaps more than one -- to ameliorate the COVID-19 pandemic may soon be in reach.

Oxford Vaccine

Those receiving the ChAdOx1 vaccine produced both T cells and antibodies, with SARS-CoV-2 spike protein-specific T-cell responses peaking on day 14, and anti-spike IgG responses rising by 28 days after vaccination, reported Andrew Pollard, PhD, of the University of Oxford in England, and colleagues, on behalf of the Oxford COVID Vaccine Trial Group.

Moreover, there were no serious adverse events, and local and systemic reactions were reduced by use of prophylactic acetaminophen in a subgroup of participants, the authors wrote in .

Interestingly, a group of 10 non-blinded volunteers also received a booster dose of vaccine 28 days after the first dose, which had neutralizing activity by day 56 in all participants, the authors noted.

Pollard explained in a statement how his group developed the vaccine, using a weakened version of an adenovirus, or a common cold virus, that attacks chimpanzees, and then genetically modifying it 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 [recognize] the SARS-CoV-2 virus," he said.

He added that the vaccine is designed to induce both antibody and T-cell responses, so it both attacks the virus while it's circulating in the body and attacks infected cells. The hope is "the immune system will remember the virus" so the vaccine "will protect people for an extended period," Pollard said.

The researchers examined 1,077 adults ages 18-55 in five British hospitals from April 23 to May 21; this includes up through day 56 of the trial, which is ongoing. Overall, 543 were randomized to receive the vaccine and 534 were randomized to receive placebo, the meningitis vaccine (MenACWY). In addition, 56 participants each in both groups received prophylactic paracetamol.

The median age of participants was 35, with a near-even split of men and women. Nearly all participants were white, and baseline characteristics were similar between groups.

Antibodies against SARS-CoV-2 spike protein peaked by day 28 and remained elevated to day 56 in the vaccine group after one dose, though they were unsurprisingly higher in the 10 participants who also received a booster dose.

Prophylactic paracetamol did appear to have an impact, as the authors noted that an adjusted analysis found that prophylactic paracetamol in the first 2 days after vaccination was associated with significant reductions in pain, feeling feverish, chills, muscle ache, headache, and malaise.

Examining the subgroup who received a booster dose of vaccine, the authors noted that the "reactogenicity profile after the second dose appeared less severe," but said the small number in the group led to wide confidence intervals.

Unsolicited adverse events during the 28 days following vaccination were predominantly mild or moderate and resolved during the follow-up period. Neutropenia, or transient hematological changes from baseline, were observed in 25 of 54 vaccine group participants versus seven of 44 placebo participants.

The researchers said the next step is to test the vaccine in different populations, including older age groups, those with comorbidities, and those at high risk of infection, such as healthcare workers.

The Oxford vaccine is being commercially developed by AstraZeneca under the name AZD1222. The company said in Britain, Brazil, and South Africa, with another to start soon in the U.S.

Chinese Vaccine Progresses to Phase II

A recombinant adenovirus type-5 vaccine was safe, and generated an immune response in nearly all healthy adult volunteers who received it, Chinese researchers found.

In a separate study in , Wei Chen, PhD, of Beijing Institute of Biotechnology, and colleagues found the Ad5-vectored vaccine produced immune responses, either T cell or antibody responses at 28 days post-vaccination.

Phase I data for this vaccine was published in May. This time, researchers looked at a "low dose" and a "high dose" of the vaccine versus placebo at a single center in Wuhan, China. Overall, 508 adults participated. Of these, 253 received a higher dose of the vaccine (1 x 10¹¹ viral particles/mL), 129 received a low dose (5 x 10¹¹ viral particles/mL), and 126 received placebo.

Participants were a mean age of around 40, half were men, but 61% were ages 18-44, 26% were ages 45-54, and 13% were ages 65 and older.

About 95% of participants in the high-dose group and 91% of participants in the low-dose group showed an antibody response at day 28 post-vaccination. Nearly all participants in both vaccine groups showed a binding antibody response by day 28, while 59% of the high-dose group and 47% of the low-dose group induced a neutralizing antibody response. Placebo participants showed no increase in antibody titers compared with baseline.

But the authors noted that because a human adenovirus was used as a vector, this may hamper immune responses to vaccination. Indeed, 52% of participants showed high pre-existing immunity to the Ad5 vector, while 48% had low pre-existing immunity. Those with a higher pre-existing immunity showed an inferior immune response, as binding and neutralizing antibody levels were around two times larger in those with low pre-existing immunity, the team said.

Adverse events were mostly mild or moderate, such as injection site pain, with 72%-74% of participants in the vaccine groups reporting adverse events versus 37% of the placebo group. A higher proportion of patients in the high-dose group developed severe reactions versus the low-dose group or placebo (9% vs 1% vs 2%, respectively). The most common severe event was fever.

Phase III And Beyond

"Dystopian realities generate utopian visions," wrote Naor Bar-Zeev, PhD, and William Moss, MD, of Johns Hopkins Bloomberg School of Public Health, in an about both studies.

They described the results of both trials as "broadly similar and promising." The editorialists also described the use of adenovirus vectors to deliver and study the vaccine as "an innovative and efficient means of vaccine development in the midst of a pandemic."

Bar-Zeev and Moss then looked ahead to phase III trials, which are planned for both these vaccine candidates, noting that they should be "rapid, pragmatic, and large enough to address efficacy in subgroups of interest."

Among the most pressing questions a phase III trial should answer include:

• Whether a single dose is sufficient in older adults or a booster is required

• Does longevity of response or rates of waning differ with a two-dose regimen?

• Are there host-specific differences in immunogenicity by age, sex, or ethnicity?

Bar-Zeev and Moss also discussed the need for "pharmacovigilance infrastructure" to monitor the safety of these vaccines, including "surveillance for asymptomatic infection among vaccinated and unvaccinated persons" to determine risk of adverse vaccine outcomes, such as enhanced disease.

Comment