FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Two Ebola vaccines were found safe and effective in separate international phase I trials involving healthy European and African adults, according to two reports published online April 27 in the New England Journal of Medicine.
After further testing and confirmation of these preliminary results, both vaccines should prove useful in both preventing and controlling future outbreaks, both research groups said.
Several vaccines showed promise in previous primate and preliminary human studies, including one expressing the surface glycoprotein of Zaire ebolavirus (ZEBOV). Different versions of this vaccine were assessed in the present phase I studies.
In the first trial, investigators sought to extend the durability of this vaccine by administering a single “priming” dose of the chimpanzee adenovirus 3 (ChAd3) vaccine encoding the ZEBOV surface glycoprotein, then giving a “booster” with a modified vaccinia Ankara (MVA) strain either 1 or 2 weeks later. The participants, 60 healthy adults aged 18-50 years, were randomly assigned to receive a low dose (20 subjects), an intermediate dose (20 subjects), or a high dose (20 subjects) of viral particles. Ten participants from each of these dose groups were then offered the booster. Then two additional groups of eight participants each were assessed to see whether giving the booster at 1 week vs. at 2 weeks made a difference in immunogenicity or safety.
All the study groups showed both antibody and T-cell immunogenicity after vaccination, but the groups that received the boosters showed antibody responses four times higher than those who did not. The MVA booster increased virus-specific antibodies by a factor of 12, and significantly increased neutralizing antibodies as well, said Dr. Katie Ewer of the Jenner Institute and Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford (England) and the National Institute for Health Research Oxford Biomedical Research Centre and her associates.
The boosters also improved the vaccine’s cell-mediated immunity, increasing glycoprotein-specific CD8+ T cells by a factor of five.
In addition, the MVA booster markedly improved the vaccine’s durability, with 100% of recipients continuing to show seropositivity at 6 months, compared with only 50%-74% of participants who did not receive the booster.
The safety profile of the vaccine and the booster were termed “acceptable” at all dose levels and at all dosing intervals studied. There were no serious adverse events, and most adverse events were self-limited and mild. Moderate systemic adverse events included transient fever, myalgia, arthralgia, headache, fatigue, nausea, and malaise. Regarding laboratory abnormalities, four patients showed prolonged activated partial-thromboplastin time without coagulopathy, all of which resolved within 10 weeks; several patients showed mild or moderate lymphocytopenia and mild or moderate elevations in bilirubin, all of which were transient.
Overall, “We found that boosting can be immunogenic for antibodies and T cells at prime-boost intervals as short as 1 week. Such short-interval regimens may facilitate vaccine deployment in outbreak settings where both rapid onset and durable vaccine efficacy are required,” Dr. Ewer and her associates noted ( N Engl J Med. 2016 Apr 27. doi: 10.1056/NEJMoa1411627 ).
They added that the ChAd3-plus-MVA viral vectors have other practical advantages. “Large-scale manufacturing processes concordant with Good Manufacturing Practice standards have been established, and both vectors have been assessed in large numbers of vaccines for a range of indications, without reports of any substantial safety concerns to date,” Dr. Ewer and her coauthors said.
The second report concerned four parallel studies: three open-label dose-escalation studies in Gabon, Kenya, and Germany and one randomized, double-blind trial in Geneva assessing the safety and immunogenicity of several doses of recombinant vesicular stomatitis virus (rVSV)-vectored ZEBOV. The 158 participants were followed for at least 6 months, said Dr. Selidji T. Agnandji of the Centre de Recherches Medicales de Lambarene (Gabon), the Institut für Tropenmedizin, Universitätsklinikum Tübingen (Germany), and the German Center for Infection Research, Tübingen, and his associates.
The vaccine was immunogenic in all participants across every dose and every study site, with higher glycoprotein-binding antibody titers at higher doses. These antibodies persisted through 6 months, a “promising” result suggesting that a single dose of this vaccine may be sufficient for early and possibly for long-term protection, the investigators said ( N Engl J Med. 2016 Apr 27. doi: 10.1056/NEJMoa1502924 ).
Although there were no serious adverse events associated with this vaccine, acute vaccine reactions were common: 92% of patients reported an acute reaction, and 10%-22% (depending on the study site) reported grade 3 symptoms. The most bothersome – and unexpected – reactions involved viral seeding of joints and skin.
The joint problems manifested as arthritis, tenosynovitis, or bursitis that appeared at a median of 11 days after injection. The arthritis tended to affect one to four peripheral joints asymmetrically; pain was usually mild and dysfunction was usually moderate. Ten of the 11 affected patients in Geneva and both of the two (out of 60) affected patients at the other sites were symptom-free by 6 months. These findings “suggest a favorable long-term prognosis for these vaccine-induced arthritides,” Dr. Agnandji and his associates said.
Three participants developed maculopapular rashes mainly affecting the limbs, which appeared at 7-9 days following injection and persisted for 1-2 weeks. The rash was accompanied by a few tender vesicles on fingers or toes. Synovial fluid extracted from affected joints and material recovered from skin vesicles showed the presence of rVSV.
Given that most adverse reactions occurred soon after vaccination, were of short duration, and were amenable to treatment, this vaccine demonstrated “a favorable risk-benefit balance,” they added.
