Local and systemic adverse events such as fatigue, headache, and local tenderness occurred commonly in Covid-19 vaccinees, but were tolerable and mostly ameliorated by paracetamol.
No serious adverse events occurred. Neutralising antibodies were generated in more than 90 percent of participants across different assays.
Responses were sustained up to 56 days of observation.
A small non-randomly selected, second-dose boosted subset showed strong neutralising responses, and few mild adverse events. Importantly, T-cell responses were induced in all participants.
Meanwhile, Wei Chen and colleagues report results from a phase 2 randomised trial of one injection of non-replicating adenovirus-vectored Covid-19 vaccine.
Vaccine formulation at two concentrations (ie, 1 × 1011 or 5 × 1010 viral particles per mL) were tested against placebo among 508 healthy COVID-19 unexposed adults (50 percent male) aged 18-83 years (mean 39.7 years) recruited from one centre in Wuhan, China, and followed up for 28 days.
Adverse events such as fever, fatigue, headache, or local site pain occurred by day 28 in 294 (77 percent) of 382 vaccines and 61 (48 percent) of 126 placebo recipients.
Male sex was associated with lower occurrence of fever post-vaccination. No serious adverse events occurred. Seroconversion occurred in more than 96 percent of participants, and neutralising antibodies were generated in about 85%.
More than 90 percent had T-cell responses. People older than 55 years of age had somewhat lower humoral responses (although still higher than placebo), as did people with previous vector immunity, but these factors did not affect T-cell responses. Immunogenicity did not differ by sex.
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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.
Overall, the results of both trials are broadly similar and promising, notwithstanding differences in the vector, in the geographical locations of the populations studied, and the neutralisation assays used.
Without drawing causal inference, the exploration of associations of age and sex with adverse events and immunogenicity reported by Chen and colleagues, and of longevity of response by Pollard and colleagues, are welcomed, given the differential burden of severe outcomes in older adults, and the emerging science around differential sex-specific vaccine effects.
These Covid-19 vaccine trials are small so inferential caution is warranted, but the explorations are laudable. Ethnic diversity in both these trials was very limited.
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.
The platform 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.
What should phase 3 trials look like?
They should be rapid, pragmatic, and large enough to address efficacy in subgroups of interest.
Will a single dose be sufficient in older adults, or is a booster dose required?
Does longevity of response or rates of waning differ with a two-dose regimen, and does longevity of clinical protection require cell-mediated responses?
Are there host-specific differences in immunogenicity by age, sex, or ethnicity?
Do T-cell responses correlate with protection irrespective of humoral titres?
Are there specific adverse events in pregnant women?
As hotspots for infection shift, trial designs that are responsive to differential risk, or that are enriched for networks of infection, should be deployed.
The safety signals from these two important trials are reassuring. But when things are urgent, we must proceed cautiously.
The success of Covid-19 vaccines hinges on community trust in vaccine sciences, which requires comprehensive and transparent evaluation of risk and honest communication of potential harms.
Hand in hand with the trajectory of vaccine study, pharmacovigilance infrastructure is urgently needed, including surveillance for asymptomatic infection among vaccinated and unvaccinated persons if both absolute and relative risk of adverse vaccine outcomes, such as enhanced disease, are to be determined.
These should be implemented in parallel with phase 3 trials and in preparation for phase 4 roll-out.
Such infrastructure will be needed across a wide range of populations and settings, and for the spectrum of upcoming Covid-19 vaccines.
Equitable distribution of future Covid-19 vaccines also requires detailed evaluation of local country needs and priorities, community engagement, and trust.
Global planning is underway, but should be underpinned and informed by specific local realities.
Only this way can these very encouraging first early-phase randomised trial results yield the global remedy for which we all yearn.
At the end of its report, the Lancet said: “We declare no competing interests.”