Safety and immunogenicity of a live attenuated influenza H5 candidate vaccine strain A/17/turkey/Turkey/05/133 H5N2 and its priming effects for potential pre-pandemic use: a randomised, double-blind, placebo-controlled trial

Abstract

SummaryBackgroundThe emergence of highly pathogenic avian influenza H5N1 viruses has raised concerns about their pandemic potential. Vaccination is the most effective way of preventing influenza. In this study, we investigated the safety and immunogenicity of an avian H5N2 live attenuated influenza vaccine (LAIV H5N2) in healthy Thai adults and its priming immune responses with an H5N1 inactivated vaccine boost.MethodsThis study was done at the Vaccine Trial Centre at Mahidol University, Bangkok, Thailand and was divided into two parts. Part 1 consisted of a randomised, double-blind, placebo-controlled trial done over 18 months. We randomly assigned (2:1) healthy Thai adults aged 18–49 years with a computer generated randomisation sequence (blocks of six) to receive either two intranasal doses (0·25 mL per nostril) of LAIV H5N2 (101 participants) or placebo (51 participants) 21 days apart. For part 2, an open-label trial was done in which previously vaccinated participants (40 from LAIV H5N2 group and 20 placebo) were given one intramuscular dose (0·5 mL) of H5N1 booster vaccine. Participants, investigators, and site-study workers were blinded from randomisation. Immune responses after subsequent immunisation were evaluated using haemagglutination-inhibition and microneutralisation assays and circulating follicular T-helper cells and plasmablast cells were measured in serum and whole blood. The trials are registered with ClinicalTrials.gov, numbers NCT01841918 and NCT02229357.FindingsBetween Feb 4, 2013, and Feb 28, 2013, 256 individuals were screened, of whom 152 participants were enrolled in part 1 of this study. LAIV H5N2 vaccine was well tolerated. Viral shedding was detected in only six (6%) of 101 participants in the vaccine group 1 day after the first vaccination and in and two (2%) of 98 participants in the group after the second vaccination. There was no serious adverse event in both groups. 51 (50%) of 101 participants in the vaccine group and 28 (55%) of 51 in the placebo group reported at least one adverse event. 80 (84%) of 95 events in the vaccine group and 32 (78%) of 43 events in the placebo groups were reportedly suspected adverse events, probably related to the vaccine; however, most were mild in nature. After two doses of vaccine, 13 (13%) of 100 participants in the vaccine group had an increase in haemagglutination-inhibition titre of more than four-fold and four (4%) of 100 vaccinees developed a rise in neutralisng antibody titre of more than four-fold. 1 year later, after a booster with an inactivated H5N1 vaccine (part 2), 39 (98%) of 40 participants who had previously been vaccinated with LAIV H5N2 had an increase in haemagglutination-inhibition titre of greater than four-fold as early as day 7 compared with three (15%) of 20 participants in the placebo group. Peak geometric mean titre (GMT) for haemagglutination-inhibition antibodies in the previously LAIV H5N2 vaccinated group (566·89 [95% CI 436·97–735·44]) were significantly higher than among those who previously received placebo (25·4...

A review of epidemic preparedness for influenza through local vaccine production: national security for Thailand

“…Eighty (84%) of 95 events in the vaccine group and 32 (78%) of 43 events in the placebo group were reported as probably related to vaccination. 10 There was no adverse event reported as definitely related to vaccination.…”

“…was observed in 3 (15%) of 20 participants in HAI assay and MN assay on day 7 (both p < .0001 vs. vaccine group) on day 28, 14 (70%) or 20 participants and 15 (75%) of 20 participants in the control group developed four-fold or greater increase in antibody titer by HAI assay and MN assay, respectively. 10 These data show the boosting effect from the priming dose of vaccine.…”

“…The detailed information about the vaccine and the study procedure was previously described. 10 Characteristics of screened volunteers Between Feb 4, 2013, and Feb 28, 2013, 256 individuals were screened, of whom 152 participants were enrolled and 104 were excluded because of abnormal laboratory tests, abnormal chest x-rays, and medical history. 10 The characteristics of the screenfailed and enrolled participants were not statistically different in terms of age, height, weight and gender composition ( Table 1).…”

“…The detailed results are described in our previous report. 10 Efforts in manufacturing inactivated influenza vaccines (IIVs)…”

Immunogenicity and protective efficacy of prime-boost immunization in mice vaccinated with live and inactivated influenza A (H5N1) vaccines

“…Однако клинические испытания потенциально пандемической ЖГВ А/17/Turkey/Turkey/05/133 (H5N2) на волонтерах показали ее невысокую иммуногенность после двукратного введения в отношении как гуморального, так и клеточного иммунного ответа [17]. В дальнейших исследованиях было установлено, что несмотря на сниженную по сравнению с сезонными штаммами иммуногенность, вакцинация формирует долговременную иммунологическую память, приводящую к усилению иммунного ответа на бустиммунизацию инактивированной гриппозной вакциной (ИГВ) А (H5N1) [16,18].…”