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Comparative Immunological Study in Mice of Inactivated Influenza Vaccines Used in the Russian Immunization Program.

ABSTRACT: A series of commercial inactivated influenza vaccines (IIVs) used in the Russian National Immunization Program were characterized to evaluate their protective properties on an animal model. Standard methods for quantifying immune response, such as hemagglutination inhibition (HAI) assay and virus neutralization (VN) assay, allowed us to distinguish the immunogenic effect of various IIVs from that of placebo. However, these standard approaches are not suitable to determine the role of various vaccine components in immune response maturation. The expanded methodological base including an enzyme-linked immunosorbent assay (ELISA) and a neuraminidase ELISA (NA-ELISA) helped us to get wider characteristics and identify the effectiveness of various commercial vaccines depending on the antigen content. Investigations conducted showed that among the IIVs tested, Ultrix^®, Ultrix^® Quadri and VAXIGRIP^® elicit the most balanced immune response, including a good NA response. For Ultrix^®, Ultrix^® Quadri, and SOVIGRIPP^® (FORT LLC), the whole-virus specific antibody subclass IgG1, measured in ELISA, seriously prevailed over IgG2a, while, for VAXIGRIP^® and SOVIGRIPP^® (NPO Microgen JSC) preparations, the calculated IgG1/IgG2a ratio was close to 1. So, the immune response varied drastically across different commercial IIVs injected in mice.

SUBMITTER: Shanko A

PROVIDER: S-EPMC7768547 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Comparative Immunological Study in Mice of Inactivated Influenza Vaccines Used in the Russian Immunization Program.

Shanko Andrei A Shuklina Marina M Kovaleva Anna A Zabrodskaya Yana Y Vidyaeva Inna I Shaldzhyan Aram A Fadeev Artem A Korotkov Alexander A Zaitceva Marina M Stepanova Liudmila L Tsybalova Liudmila L Kordyukova Larisa L Katlinski Anton A

Vaccines 20201212 4

A series of commercial inactivated influenza vaccines (IIVs) used in the Russian National Immunization Program were characterized to evaluate their protective properties on an animal model. Standard methods for quantifying immune response, such as hemagglutination inhibition (HAI) assay and virus neutralization (VN) assay, allowed us to distinguish the immunogenic effect of various IIVs from that of placebo. However, these standard approaches are not suitable to determine the role of various vac ...[more]

PMID: 33322762

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Project description:BACKGROUND:today's standard quality control methods used to control the protein composition of inactivated influenza vaccines only take into account a few key reference components. They do not allow for thorough characterization of protein compositions. As a result, observation of unpredictable variations in major viral constituents and admixtures of cellular proteins within manufactured vaccines that may seriously influence the immunogenicity and safety of such vaccines has become a pressing issue in vaccinology. This study aims at testing a more sophisticated approach for analysis of inactivated split influenza vaccines licensed in the Russian Federation. The formulations under study are the most available on the market and are included in the Russian National Immunization Program. METHODS:liquid chromatography with tandem mass spectrometry (LC-MS/MS) analysis, in combination with label-free protein quantitation via the intensity-based absolute-quantitation (iBAQ) algorithm, as well as a number of standard molecular analysis methods, such as sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE), dynamic light scattering (DLS), and negative-stain transmission electron microscopy (TEM) were applied. RESULTS:the methods implemented were able to identify dozens of viral and host proteins and quantify their relative amounts within the final formulations of different commercially available inactivated split influenza vaccines. Investigation of molecular morphology of the vaccine preparations using TEM revealed typical rosettes of major surface proteins (hemagglutinin and neuraminidase). DLS was used to demonstrate a size distribution of the rosettes and to test the stability of vaccine preparations at increased temperatures. CONCLUSIONS:a holistic approach based on modern, highly productive analytical procedures was for the first time applied for a series of different commercially available inactivated split influenza vaccines licensed in Russia. The protocols probed may be suggested for the post-marketing quality control of vaccines. Comparison of different preparations revealed that the Ultrix® and Ultrix® Quadri vaccines produced by pharmaceutical plant FORT LLC and trivalent vaccine Vaxigrip® produced by pharmaceutical company Sanofi Pasteur have well-organized antigen rosettes, they contain fewer admixture quantities of host cell proteins, and demonstrate good correlation among mostly abundant viral proteins detected by different methods.

Project description:BackgroundEnterovirus 71 (EV71) is the major causative agent of hand, foot, and mouth disease (HFMD). Three inactivated EV71 whole-virus vaccines of different strains developed by different manufacturers in mainland China have recently entered clinical trials. Although several studies on these vaccines have been published, a study directly comparing the immunogenicity and protective effects among them has not been carried out, which makes evaluating their relative effectiveness difficult. Thus, properly comparing newly developed vaccines has become a priority, especially in China.Methods and findingsThis comparative immunogenicity study was carried out on vaccine strains (both live and inactivated), final container products (FCPs) without adjuvant, and corresponding FCPs containing adjuvant (FCP-As) produced by three manufacturers. These vaccines were evaluated by neutralizing antibody (NAb) responses induced by the same or different dosages at one or multiple time points post-immunization. The protective efficacy of the three vaccines was also determined in one-day-old ICR mice born to immunized female mice. Survival rates were observed in these suckling mice after challenge with 20 LD(50) of EV71/048M3C2. Three FCP-As, in a dose of 200 U, generated nearly 100% NAb positivity rates and similar geometric mean titers (GMTs), especially at 14-21 days post-inoculation. However, the dynamic NAb responses were different among three vaccine strains or three FCPs. The FCP-As at the lowest dose used in clinical trials (162 U) showed good protective effects in suckling mice against lethal challenge (90-100% survival), while the ED(50) of NAb responses and protective effects varied among three FCP-As.ConclusionsThese studies establish a standard method for measuring the immunogenicity of EV71 vaccines in mice. The data generated from our mouse model study indicated a clear dose-response relationship, which is important for vaccine quality control and assessment, especially for predicting protective efficacy in humans when combined with future clinical trial results.

Project description:Avian influenza viruses of the H7 hemagglutinin (HA) subtype present a significant public health threat, as evidenced by the ongoing outbreak of human A(H7N9) infections in China. When evaluated by hemagglutination inhibition (HI) and microneutralization (MN) assays, H7 viruses and vaccines are found to induce lower level of neutralizing antibodies (nAb) than do their seasonal counterparts, making it difficult to develop and evaluate prepandemic vaccines. We have previously shown that purified recombinant H7 HA appear to be poorly immunogenic in that they induce low levels of HI and MN antibodies. In this study, we immunized mice with whole inactivated reverse genetics reassortant (RG) viruses expressing HA and neuraminidase (NA) from 3 different H7 viruses [A/Shanghai/2/2013(H7N9), A/Netherlands/219/2003(H7N7), and A/New York/107/2003(H7N2)] or with human A(H1N1)pdm09 (A/California/07/2009-like) or A(H3N2) (A/Perth16/2009) viruses. Mice produced equivalent titers of antibodies to all viruses as measured by enzyme-linked immunosorbent assay (ELISA). However, the antibody titers induced by H7 viruses were significantly lower when measured by HI and MN assays. Despite inducing very low levels of nAb, H7 vaccines conferred complete protection against homologous virus challenge in mice, and the serum antibodies directed against the HA head region were capable of mediating protection. The apparently low immunogenicity associated with H7 viruses and vaccines may be at least partly related to measuring antibody titers with the traditional HI and MN assays, which may not provide a true measure of protective immunity associated with H7 immunization. This study underscores the need for development of additional correlates of protection for prepandemic vaccines.IMPORTANCE H7 avian influenza viruses present a serious risk to human health. Preparedness efforts include development of prepandemic vaccines. For seasonal influenza viruses, protection is correlated with antibody titers measured by hemagglutination inhibition (HI) and virus microneutralization (MN) assays. Since H7 vaccines typically induce low titers in HI and MN assays, they have been considered to be poorly immunogenic. We show that in mice H7 whole inactivated virus vaccines (WIVs) were as immunogenic as seasonal WIVs, as they induced similar levels of overall serum antibodies. However, a larger fraction of the antibodies induced by H7 WIV was nonneutralizing in vitro Nevertheless, the H7 WIV completely protected mice against homologous viral challenge, and antibodies directed against the HA head were the major contributor toward immune protection. Vaccines against H7 avian influenza viruses may be more effective than HI and virus neutralization assays suggest, and such vaccines may need other methods for evaluation.

Project description:BackgroundThis costing study in Malawi is a first evaluation of a Maternal Influenza Immunization Program Costing Tool (Costing Tool) for maternal immunization. The tool was designed to help low- and middle-income countries plan for maternal influenza immunization programs that differ from infant vaccination programs because of differences in the target population and potential differences in delivery strategy or venue.MethodsThis analysis examines the incremental costs of a prospective seasonal maternal influenza immunization program that is added to a successful routine childhood immunization and antenatal care program. The Costing Tool estimates financial and economic costs for different vaccine delivery scenarios for each of the major components of the expanded immunization program.ResultsIn our base scenario, which specifies a donated single dose pre-filled vaccine formulation, the total financial cost of a program that would reach 2.3 million women is approximately $1.2 million over five years. The economic cost of the program, including the donated vaccine, is $10.4 million over the same period. The financial and economic costs per immunized pregnancy are $0.52 and $4.58, respectively. Other scenarios examine lower vaccine uptake, reaching 1.2 million women, and a vaccine purchased at $2.80 per dose with an alternative presentation.ConclusionThis study estimates the financial and economic costs associated with a prospective maternal influenza immunization program in a low-income country. In some scenarios, the incremental delivery cost of a maternal influenza immunization program may be as low as some estimates of childhood vaccination programs, assuming the routine childhood immunization and antenatal care systems are capable of serving as the platform for an additional vaccination program. However, purchasing influenza vaccines at the prices assumed in this analysis, instead of having them donated, is likely to be challenging for lower-income countries. This result should be considered as a starting point to understanding the costs of maternal immunization programs in low- and middle-income countries.

Dataset Information

Comparative Immunological Study in Mice of Inactivated Influenza Vaccines Used in the Russian Immunization Program.

Publications

Comparative Immunological Study in Mice of Inactivated Influenza Vaccines Used in the Russian Immunization Program.

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