Preliminary Assessment of Safety and Immunogenicity of an Inactivated Whole-Virion Vaccine against Influenza А (H1N1) Pdm09 Containing Aluminum Hydroxide Adjuvant: A Randomized, Blinded Phase I Clinical Study

Abstract

We performed a randomized, blinded, dose-dependent placebo-controlled phase I clinical study of single administration of Refluvac®, a monovalent inactivated whole-virion vaccine against pandemic influenza А (Н1N1) pdm09 containing aluminum adjuvant, in healthy volunteers aged 18-60. Single intramuscular injection at doses of 3.75, 7.5, or 15.0 µg hemagglutinin (НА) identified no safety issues in adult volunteers (n=12 per group); no severe or serious vaccination-related adverse events were observed. Only mild/moderate local adverse events (n= 3/12, 25% in 7.5 µg НА arm,) and one moderate systemic reaction (n=1/12, 8.3% in 15.0 µg НА arm) were observed. In volunteers vaccinated at 3.75 µg HA, the proportion of subjects with 4-fold seroconversion was 75%, the level of seroprotection was also 75%, the antibody titer increase was 10.7-fold, and the geometric mean titer (GMT) of antibodies to А/H1N1p-dm09 was 53.4; for the 7.5 µg HA dose, the proportion of 4-fold seroconversion was 75%, the antibody titer increase was 32.0-fold, the GMT was 160.0, and the level of seroprotection was 75%. When administered at a higher dose (15 µg HA), the proportion of subjects with protective antibody titers increased from 75% to 83%; however, the GMT and antibody titer increase were not significantly different (P>0.05) to the group vaccinated at 7.5 µg HA. Phase II clinical studies of the 3.75 and 7.5 µg HA doses of Refluvac® vaccine should be performed in a larger cohort of healthy volunteers aged 18-60. The effective immunogenicity of low doses of Refluvac® vaccine may enable increased production of pandemic influenza vaccines, and thus provide more people with a safe, effective vaccine. Citation: Tabynov K, Khairullin B, Kydyrbayev Z, Sandybayev N, Stukova M, et al. (2013) [16]. Notably, the lowest НА content required to induce a sufficient immune response was seen when whole-virion or adjuvant-containing vaccines were used. The НА content is the most important limiting factor when developing a pandemic vaccine, as existing production capacities for seasonal influenza vaccines are rather limited and are unable to meet the worldwide demand for a pandemic vaccine. Thus, a higher number of doses of vaccines with low antigenic loads can be manufactured. Journal of Vaccines & VaccinationOn this basis, in order to create a pandemic vaccine to protect the population of Kazakhstan and neighbouring Central Asian countries, an inactivated whole-virion vaccine (Refluvac®) against Н1N1pdm09 containing aluminum hydroxide adjuvant was developed at the Research Institute for Biological Safety Problems (Kazakhstan). We previously demonstrated the safety and immunogenicity of this vaccine in preclinical studies conducted at research centers in Russia (The Research Institute of Influenza, Institute of Toxicology, Chemical and Pharmaceutical Academy) and Kazakhstan (The National Center for Expertise on Drugs) [17,18]. On the basis of these preclinical studies, Refluvac® vaccine was recommended for a phase I clinical study of single intra...

Immunogenicity and safety of a novel seasonal influenza preservative-free vaccine manufactured in Kazakhstan: Results of a randomized, comparative, phase II clinical trial in adults

“…The Republic of Kazakhstan will be the first among them to produce its own influenza vaccines including pandemic ones. 5,6 An inactivated allantoic split vaccine against seasonal influenza (RIBSP vaccine) for seasonal influenza prophylaxis has been developed in the Research Institute for Biological Safety Problems. 7,8 This vaccine is easily manufactured and was shown to be safe and highly immunogenic.…”

Safety and immunogenicity of the novel seasonal preservative‐ and adjuvant‐free influenza vaccine: Blind, randomized, and placebo‐controlled trial

“…9,10 Because of territorial disposition and natural climatic conditions Pursuant to the strategic plan of providing Kazakhstanean population with sufficient stock of vaccine against pandemic influenza the inactivated whole virus adjuvant vaccine Refluvac® against influenza A(Н1N1) pdm09 virus and pandemic whole virus adjuvant vaccine Kazfluvac® against avian influenza A/Н5N1 virus were developed, tested and registered. [11][12][13] To ensure seasonal influenza prophylaxis in the Republic of Kazakhstan the Research Institute for Biological Safety Problems has developed a seasonal influenza split vaccine that is available for manufacturing as well as reliable for safety and immunogenicity. 14…”

“…SafetyWithin May[11][12][13][14][15][16][17][18][19][20][21][22][23][24][25] 2016 in total 88 volunteers were screened for fitting inclusion/exclusion criteria of the trial. Anamneses of all screened persons were collected, physical examination of volunteers was carried out, their primary physiological characteristics were determined (height, weight, body temperature, blood pressure, pulse/ heart rate, and breathing rate), ECG data were obtained, venous blood for clinical, biochemical, and immunological assays was sampled, urine from all volunteers was analyzed, women were tested for pregnancy.…”