Trivalent Live Attenuated Influenza Vaccine Research Articles

Development of Cross-Reactive Live Attenuated Influenza Vaccine Candidates against Both Lineages of Influenza B Virus.

Influenza viruses continue to cause a significant social and economic burden globally. Vaccination is recognized as the most effective measure to control influenza. Live attenuated influenza vaccines (LAIVs) are an effective means of preventing influenza, especially among children. A reverse genetics (RG) system is required to rapidly update the antigenic composition of vaccines, as well as to design LAIVs with a broader spectrum of protection. Such a system has been developed for the Russian LAIVs only for type A strains, but not for influenza B viruses (IBV). All genes of the B/USSR/60/69 master donor virus (B60) were cloned into RG plasmids, and the engineered B60, as well as a panel of IBV LAIV reassortants were rescued from plasmid DNAs encoding all viral genes. The engineered viruses were evaluated in vitro and in a mouse model. The B60 RG system was successfully developed, which made it possible to rescue LAIV reassortants with the desired antigenic composition, including hybrid strains with hemagglutinin and neuraminidase genes belonging to the viruses from different IBV lineages. The LAIV candidate carrying the HA of the B/Victoria-lineage virus and NA from the B/Yamagata-lineage virus demonstrated optimal characteristics in terms of safety, immunogenicity and cross-protection, prompting its further assessment as a broadly protective component of trivalent LAIV. The new RG system for B60 MDV allowed the rapid generation of type B LAIV reassortants with desired genome compositions. The generation of hybrid LAIV reassortants with HA and NA genes belonging to the opposite IBV lineages is a promising approach for the development of IBV vaccines with broad cross-protection.

Technical guidelines for seasonal influenza vaccination in China (2023-2024)

Technical guidelines for seasonal influenza vaccination in China (2023-2024)

Technical guidelines for seasonal influenza vaccination in China (2022-2023)

Technical guidelines for seasonal influenza vaccination in China (2022-2023)

Technical guidelines for seasonal influenza vaccination in China (2022-2023)

Technical guidelines for seasonal influenza vaccination in China (2022-2023)

Prior upregulation of interferon pathways in the nasopharynx impacts viral shedding following live attenuated influenza vaccine challenge in children

SummaryIn children lacking influenza-specific adaptive immunity, upper respiratory tract innate immune responses may influence viral replication and disease outcome. We use trivalent live attenuated influenza vaccine (LAIV) as a surrogate challenge model in children aged 24–59 months to identify pre-infection mucosal transcriptomic signatures associated with subsequent viral shedding. Upregulation of interferon signaling pathways prior to LAIV is significantly associated with lower strain-specific viral loads (VLs) at days 2 and 7. Several interferon-stimulated genes are differentially expressed in children with pre-LAIV asymptomatic respiratory viral infections and negatively correlated with LAIV VLs. Upregulation of genes enriched in macrophages, neutrophils, and eosinophils is associated with lower VLs and found more commonly in children with asymptomatic viral infections. Variability in pre-infection mucosal interferon gene expression in children may impact the course of subsequent influenza infections. This variability may be due to frequent respiratory viral infections, demonstrating the potential importance of mucosal virus-virus interactions in children.

Technical guidelines for seasonal influenza vaccination in China (2021-2022)

Technical guidelines for seasonal influenza vaccination in China (2021-2022)

The effect of live attenuated influenza vaccine on pneumococcal colonisation densities among children aged 24–59 months in The Gambia: a phase 4, open label, randomised, controlled trial

SummaryBackgroundInfluenza and other respiratory viruses promote Streptococcus pneumoniae proliferation in the upper respiratory tract. We sought to investigate for what we believe is the first time, the effect of intranasal live attenuated influenza vaccine (LAIV) on nasopharyngeal S pneumoniae density in a low-income to middle-income country population with high pneumococcal carriage rates.MethodsIn an open-label, randomised, controlled trial in The Gambia, 330 healthy children aged 24–59 months were randomly assigned 2:1 to receive one trivalent LAIV dose at enrolment (day 0, intervention) or at the end of active follow-up (day 21, control). The investigator team were initially masked to block size and randomisation sequence to avoid allocation bias. Group allocation was later revealed to the investigator team. The primary outcome was PCR-quantified day 7 and 21 pneumococcal density. Asymptomatic respiratory viral infection at baseline and LAIV strain shedding were included as covariates in generalised mixed-effects models, to assess the effect of LAIV and other variables on pneumococcal densities. The study is registered at ClinicalTrials.gov, NCT02972957, and is closed to recruitment.FindingsBetween Feb 8 and April 12, 2017, and Jan 15 and March 28, 2018, of 343 children assessed for eligibility, 213 in the intervention group and 108 in the control group completed the study and were included in the final analysis. Although no significant differences were seen in pneumococcal carriage or density at each timepoint when comparing groups, changes from baseline were observed in the LAIV group. The baseline S pneumoniae carriage prevalence was high in both LAIV and control groups (75%) and increased by day 21 in the LAIV group (85%, p=0·0037), but not in the control group (79%, p=0·44). An increase in pneumococcal density from day 0 amounts was seen in the LAIV group at day 7 (+0·207 log10 copies per μL, SE 0·105, p=0·050) and day 21 (+0·280 log10 copies per μL, SE 0·105, p=0·0082), but not in the control group. Older age was associated with lower pneumococcal density (−0·015 log10 copies per μL, SE 0·005, p=0·0030), with the presence of asymptomatic respiratory viruses at baseline (+0·259 log10 copies per μL, SE 0·097, p=0·017), and greater LAIV shedding at day 7 (+0·380 log10 copies per μL, SE 0·167, p=0·024) associated with higher pneumococcal density. A significant increase in rhinorrhoea was reported in the LAIV group compared with the control group children during the first 7 days of the study (103 [48%] of 213, compared with 25 [23%] of 108, p<0·0001), and between day 7 and 21 (108 [51%] of 213, compared with 28 [26%] of 108, p<0·0001).InterpretationLAIV was associated with a modest increase in nasopharyngeal pneumococcal carriage and density in the 21 days following vaccination, with the increase in density lower in magnitude than previously described in the UK. This increase was accelerated when LAIV was administered in the presence of pre-existing asymptomatic respiratory viruses, suggesting that nasopharyngeal S pneumoniae proliferation is driven by cumulative mixed-viral co-infections. The effect of LAIV on pneumococcal density is probably similar to other respiratory viral infections in children. Our findings provide reassurance for the use of LAIV to expand influenza vaccine programmes in low-income to middle-income country populations with high pneumococcal carriage.FundingWellcome Trust.

Pre-Existing Upregulation of Interferon Pathways in the Nasopharynx Impacts Viral Shedding Following Live Attenuated Influenza Vaccine Challenge in Children

Rationale: In children lacking adaptive immunity to influenza, upper respiratory tract innate immune responses may be important and explain variability in viral shedding and disease outcome. Objectives: We used live attenuated influenza vaccine (LAIV) as a surrogate challenge model in children to identify pre-infection mucosal transcriptomic signatures associated with subsequent viral shedding. We also determined whether asymptomatic respiratory viral infection impact these signatures. Methods: Children aged 24-59 months (n=82) were given one dose of trivalent LAIV during a prospective, observational, phase 4 study in The Gambia (NCT02972957). Nasopharyngeal swabs were used to determine gene expression and asymptomatic respiratory viral infection prior to challenge, and LAIV viral loads at day 2 and 7. Gene set enrichment analysis was used to identify transcriptomic signatures representing gene pathways and cell types at baseline associated with subsequent LAIV viral load. Main Results: In children seronegative for each influenza strain, upregulation of interferon signaling pathways prior to LAIV receipt was significantly associated with lower strain-specific viral loads at day 2 and 7. Asymptomatic respiratory viruses were detected in 42% of children. Several interferon-stimulated genes were differentially expressed in children with asymptomatic respiratory viral infection and negatively correlated with LAIV viral loads. Upregulation of genes enriched in macrophages, neutrophils and eosinophils was also associated with lower viral loads, and found more commonly in children with asymptomatic non-influenza viral infections. Conclusions: Variability in mucosal interferon gene expression prior to infection in children may impact the course of subsequent influenza infections. This variability may be due to frequent asymptomatic respiratory viral infections, demonstrating the potential importance of virus-virus interactions in the upper respiratory tract in determining the outcome of respiratory viral infections in children.

Technical guidelines for seasonal influenza vaccination in China (2020-2021)

Influenza virus infection is a respiratory infectious disease that can seriously affect human health. Influenza viruses can have frequent antigenic variation and changes, which can result in rapid and widespread transmission resulting in annual epidemics and outbreaks in places of public gathering such as schools, kindergartens and nursing homes. According to WHO estimation, seasonal influenza epidemics have caused an annually 3 to 5 million severe cases and 290 000 to 650 000 deaths globally. Pregnant women, young children, the elderly, and persons with chronic illnesses are at high risk for severe illness and death associated with influenza virus infection. Especially, COVID-19 pandemic might co-circulate with other respiratory infectious diseases such as influenza in the coming winter-spring season. Seasonal influenza vaccination is the most effective way to prevent influenza virus infection and complications from infection. Currently, China has licensed trivalent inactivated influenza vaccine (IIV3) which includes split-virus influenza vaccine and subunit vaccine, quadrivalent inactivated influenza vaccine (IIV4) which is split, and trivalent live attenuated influenza vaccine (LAIV3) which was newly licensed. Except for a few major cities, influenza vaccine is a category Ⅱ vaccine, which means influenza vaccination is voluntary, and recipients must pay for it. In 2018 and 2019, the China CDC issued the "Technical Guidelines for Seasonal Influenza Vaccination in China" . In the past year, new research evidences home and abroad have been published, and new seasonal influenza vaccine has been licensed in China. To strengthen the technical guidance for prevention and control of influenza and operational research on influenza vaccination in China, the National Immunization Advisory Committee (NIAC) Influenza Vaccination Technical Working Group (TWG), updated the 2019-2020 technical guidelines and compiled the "Technical guidelines for seasonal influenza vaccination in China (2020-2021)" . The main updates in this version include the following: First, new research evidences especially studies of China, including disease burden, effectiveness, Vaccine-avoidable disease burden, vaccine safety monitoring, and cost-effectiveness and cost-benefit. Second, policies and measures for influenza prevention and control issued by National Health Commission (PRC) in the past year. Thirdly, new type seasonal influenza vaccine licensed and issued in 2020-2021 in China. Fourth, northern hemisphere influenza vaccination composition for the 2020-2021 season which included trivalent and quadrivalent influenza vaccine. Fifth, Influenza vaccination recommendations for 2020-2021 influenza season. The recommendations described in this report include the following: Points of Vaccination clinics (PoVs) should provide influenza vaccination to all persons aged 6 months and above who are willing to be vaccinated and do not have contraindications. No preferential recommendation is made for one influenza vaccine product over another for persons for whom more than one licensed, recommended, and appropriate product is available. Considering the situation of globally pandemic of COVID-19, to decrease the risk of influenza virus infection and minimize the impact on COVID-19 prevention and control, we recommend the following priority for seasonal influenza vaccination: healthcare workers, including clinical doctors and nurses, public health professionals, quarantine professionals; vulnerable groups living in nursing homes or welfare homes and staffs who take care those vulnerable groups; people work or stay in high population density places, such as teachers and students in kindergartens, primary and secondary school, prisoners and staffs of prisons; other high risk group of influenza, including adults ≥60 years of age, children aged 6-59 months, persons with specific chronic diseases, the family members and caregivers of infants <6 months of age, and pregnant women or women who plan to become pregnant during the influenza season. Children aged 6 months through 8 years require 2 doses of influenza vaccine administered a minimum of 4 weeks apart during their first season of vaccination for optimal protection. People whoever get IIV or LAIV all apply to the principle. If they were vaccinated in 2019-2020 influenza season or a prior season, 1 dose is recommended. People more than 8 years old require 1 dose of influenza vaccine. It is recommended that people receive their influenza vaccination by the end of October. Influenza vaccination should be offered as soon as the vaccination is available. For the people unable to be vaccinated before the end of October, influenza vaccination will continue to be offered for the whole season. Influenza vaccine is also recommended for use in pregnant women during any trimester. These guidelines are intended for use by staff members of the CDCs at all levels who work on influenza control and prevention, PoVs staff members, healthcare workers from the departments of pediatrics, internal medicine, and infectious diseases, and staff members of maternity and child care institutions at all levels. These guidelines will be updated periodically as new evidence becomes available.

Technical guidelines for seasonal influenza vaccination in China (2020-2021)

Influenza virus infection is a respiratory infectious disease that can seriously affect human health. Influenza viruses can have frequent antigenic variation and changes, which can result in rapid and widespread transmission resulting in annual epidemics and outbreaks in places of public gathering such as schools, kindergartens and nursing homes. The World Health Organization (WHO) estimated that seasonal influenza epidemics have caused an annual 3 to 5 million severe cases, and 290000 to 650000 deaths globally. Pregnant women, young children, the elderly, and persons with chronic illnesses are at high risk for severe illness and death associated with influenza virus infection. Especially, COVID-19 pandemic might co-circulate with other respiratory infectious diseases such as influenza in the coming winter-spring season. Seasonal influenza vaccination is the most effective way to prevent influenza virus infection and complications from infection. Currently, China has licensed trivalent inactivated influenza vaccine (IIV3) which includes split-virus influenza vaccine and subunit vaccine, quadrivalent inactivated influenza vaccine (IIV4) which is split, and trivalent live attenuated influenza vaccine(LAIV3) which was newly licensed. Except for a few major cities, influenza vaccine is a category Ⅱ vaccine, which means influenza vaccination is voluntary, and recipients must pay for it. In 2018 and 2019, the Chinese Center for Disease Control and Prevention issued the"Technical Guidelines for Seasonal Influenza Vaccination in China". In the past year, new research evidences home and abroad have been published, and new seasonal influenza vaccine has been licensed in China. To strengthen the technical guidance for prevention and control of influenza and operational research on influenza vaccination in China, the National Immunization Advisory Committee (NIAC) Influenza Vaccination Technical Working Group (TWG), updated the 2019-2020 technical guidelines and compiled the "Technical guidelines for seasonal influenza vaccination in China (2020-2021)". The main updates in this version include the following: First, new research evidences especially studies of China, including disease burden, effectiveness, Vaccine-avoidable disease burden, vaccine safety monitoring, and cost-effectiveness and cost-benefit. Second, policies and measures for influenza prevention and control issued by National Health Commission(PRC)in the past year. Thirdly, new type seasonal influenza vaccine licensed and issued in 2020-2021 in China. Fourth, northern hemisphere influenza vaccination composition for the 2020-2021 season which included trivalent and quadrivalent influenza vaccine. Fifth, Influenza vaccination recommendations for 2020-2021 influenza season. The recommendations described in this report include the following: Points of Vaccination clinics (PoVs) should provide influenza vaccination to all persons aged 6 months and above who are willing to be vaccinated and do not have contraindications. No preferential recommendation is made for one influenza vaccine product over another for persons for whom more than one licensed, recommended, and appropriate product is available. Considering the situation of globally pandemic of COVID-19, to decrease the risk of influenza virus infection and minimize the impact on COVID-19 prevention and control, we recommend the following priority for seasonal influenza vaccination: (1) healthcare workers, including clinical doctors and nurses, public health professionals, quarantine professionals; (2) Vulnerable groups living in nursing homes or welfare homes and staffs who take care those vulnerable groups; (3) People in some key places, such as teachers and students in kindergartens, primary and secondary school, prisoners and staffs of prisons; (4) Other high risk group of influenza, including adults ≥60 years of age, children aged 6-59 months, persons with specific chronic diseases, the family members and caregivers of infants <6 months of age, and pregnant women or women who plan to become pregnant during the influenza season. Children aged 6 months through 8 years require 2 doses of influenza vaccine administered a minimum of 4 weeks apart during their first season of vaccination for optimal protection. People whoever get IIV or LAIV all apply to the principle. If they were vaccinated in 2019-2020 influenza season or a prior season, 1 dose is recommended. People more than 8 years old require 1 dose of influenza vaccine. It is recommended that people receive their influenza vaccination by the end of October. Influenza vaccination should be offered as soon as the vaccination is available. For the people unable to be vaccinated before the end of October, influenza vaccination will continue to be offered for the whole season. Influenza vaccine is also recommended for use in pregnant women during any trimester. These guidelines are intended for use by staff members of the Centers for Disease Control and Prevention at all levels who work on influenza control and prevention, PoVs staff members, healthcare workers from the departments of pediatrics, internal medicine, and infectious diseases, and staff members of maternity and child care institutions at all levels. These guidelines will be updated periodically as new evidence becomes available.

Genetic Basis of Attenuation of Cold-Adapted Influenza Strain B/Leningrad/14/17/55 - Backup Master Donor Virus for Influenza Type B Live Attenuated Vaccines.

The reassortant vaccine strain of live attenuated influenza vaccine inherits temperature sensitivity and areactogenicity from cold-adapted attenuated master donor virus. In Russia, B/ USSR/60/69 master donor virus (B60) is currently in use for the preparation of live attenuated type B influenza vaccine candidates. Trivalent live attenuated influenza vaccine based on A/ Leningrad/134/17/57 and B60 are licensed for the use in Russia for single dose vaccination of adults and children over 3 years. B/Leningrad/14/17/55 (B14) cold-adapted virus is a backup master donor virus for live attenuated type B influenza vaccine. According to our preliminary estimates, it is more attenuated than B60, which can allow expanding applicability of this vaccine for children under 3 years of age. In this paper, the role of B14 genes in its attenuation was assessed. Representative collection of reassortants of B14 with epidemic influenza B viruses was obtained, a phenotypic analysis of reassortants was performed, and their pathogenicity for animals was assessed. The leading role of PB2 and PA genes in attenuation of B14 master donor virus was proven.

Meta-analysis on effectiveness of live attenuated influenza vaccine against seasonal influenza in children

Objective: To evaluate the effectiveness of live attenuated influenza vaccine (LAIV) in the prevention of seasonal influenza in children aged 2-17 years. Methods: Literature retrieval of case-control studies on the effectiveness of LAIV against seasonal influenza in children published from January 2003 to November 2018 was conducted through Web of Science, PubMed, and ScienceDirect databases. The Stata 13.1 software was used for Meta-analysis. Results: A total of 14 studies were included in this study, and all were test-negative design (TND) studies. Our Meta-analysis showed that the effectiveness of LAIV in children was 49% (95%CI: 40%-57%). Subgroup analysis found that the protection rate of LAIV was 35% against influenza A (H1N1) pdm09 (95%CI: 5%-56%), 35% against influenza A (H3N2) (95%CI: 21%-46%), and 71% against influenza B (95%CI: 55%-82%). The protection rates of trivalent LAIV and quadrivalent LAIV in children were 56% (95%CI: 48%-63%) and 44% (95%CI: 27%-57%), respectively. The protection rates of LAIV in Europe and North America were 65% (95%CI: 47%-77%) and 46% (95%CI: 36%-55%), respectively. Conclusion: LAIV has a certain preventive effect on seasonal influenza in children aged 2-17 years.

Functional immune response to influenza H1N1 in children and adults after live attenuated influenza virus vaccination.

Influenza virus is a major respiratory pathogen, and vaccination is the main method of prophylaxis. In 2012, the trivalent live attenuated influenza vaccine (LAIV) was licensed in Europe for use in children. Vaccine-induced antibodies directed against the main viral surface glycoproteins, haemagglutinin (HA) and neuraminidase (NA) play important roles in limiting virus infection. The objective of this study was to dissect the influenza-specific antibody responses in children and adults, and T cell responses in children induced after LAIV immunization to the A/H1N1 virus. Blood samples were collected pre- and at 28 and 56days post-vaccination from 20 children and 20 adults. No increase in micro-neutralization (MN) antibodies against A/H1N1 was observed after vaccination. A/H1N1 stalk-specific neutralizing and NA-inhibiting (NI) antibodies were boosted in children after LAIV. Interferon γ-producing T cells increased significantly in children, and antibody-dependent cellular-mediated cytotoxic (ADCC) cell activity increased slightly in children after vaccination, although this change was not significant. The results indicate that the NI assay is more sensitive to qualitative changes in serum antibodies after LAIV. There was a considerable difference in the immune response in children and adults after vaccination, which may be related to priming and previous influenza history. Our findings warrant further studies for evaluating LAIV vaccination immunogenicity.

Comparative Immunogenicity of the 2014-2015 Northern Hemisphere Trivalent IIV and LAIV against Influenza A Viruses in Children.

Both inactivated influenza vaccines (IIV) and live-attenuated influenza vaccines (LAIV) have been recommended for administration to children. Children are a high-risk group for severe influenza, and a major source of transmission. Therefore, prevention of infection by vaccination is particularly important. However, efficacy and immunogenicity of these vaccines are known to vary by season and geographic location. We compared the immunogenicity of the 2014–2015 Northern Hemisphere trivalent IIV and LAIV against influenza A virus in Canadian Hutterite children aged 2 to 17 using hemagglutination inhibition (HAI) assays, and enzyme-linked immunosorbent assays to measure hemagglutinin-specific serum IgA and mucosal IgA. Both vaccine formulations induced significant increases in HAI titers against H1N1 and H3N2 vaccine strains. Serum IgA titers against H3N2 were significantly boosted by both IIV and LAIV, while only IIV induced a significant increase in serum IgA specific to the H1N1 vaccine strain. While HAI titers correlated with protection conferred by IIV, mucosal IgA titers correlated with protection conferred by LAIV (mucosal IgA titers could not be established as a correlate for IIV due to sample size limitations). IIV and LAIV were previously reported to be equally efficacious in this cohort, although the immunogenicity of IIV was generally superior.

Effect of a Russian-backbone live-attenuated influenza vaccine with an updated pandemic H1N1 strain on shedding and immunogenicity among children in The Gambia: an open-label, observational, phase 4 study

SummaryBackgroundThe efficacy and effectiveness of the pandemic H1N1 (pH1N1) component in live attenuated influenza vaccine (LAIV) is poor. The reasons for this paucity are unclear but could be due to impaired replicative fitness of pH1N1 A/California/07/2009-like (Cal09) strains. We assessed whether an updated pH1N1 strain in the Russian-backbone trivalent LAIV resulted in greater shedding and immunogenicity compared with LAIV with Cal09.MethodsWe did an open-label, prospective, observational, phase 4 study in Sukuta, a periurban area in The Gambia. We enrolled children aged 24–59 months who were clinically well. Children received one dose of the WHO prequalified Russian-backbone trivalent LAIV containing either A/17/California/2009/38 (Cal09) or A/17/New York/15/5364 (NY15) based on their year of enrolment. Primary outcomes were the percentage of children with LAIV strain shedding at day 2 and day 7, haemagglutinin inhibition seroconversion, and an increase in influenza haemagglutinin-specific IgA and T-cell responses at day 21 after LAIV. This study is nested within a randomised controlled trial investigating LAIV–microbiome interactions (NCT02972957).FindingsBetween Feb 8, 2017, and April 12, 2017, 118 children were enrolled and received one dose of the Cal09 LAIV from 2016–17. Between Jan 15, 2018, and March 28, 2018, a separate cohort of 135 children were enrolled and received one dose of the NY15 LAIV from 2017–18, of whom 126 children completed the study. Cal09 showed impaired pH1N1 nasopharyngeal shedding (16 of 118 children [14%, 95% CI 8·0–21·1] with shedding at day 2 after administration of LAIV) compared with H3N2 (54 of 118 [46%, 36·6–55·2]; p<0·0001) and influenza B (95 of 118 [81%, 72·2–87·2]; p<0·0001), along with suboptimal serum antibody (seroconversion in six of 118 [5%, 1·9–10·7]) and T-cell responses (CD4+ interferon γ-positive and/or CD4+ interleukin 2-positive responses in 45 of 111 [41%, 31·3–50·3]). After the switch to NY15, a significant increase in pH1N1 shedding was seen (80 of 126 children [63%, 95% CI 54·4–71·9]; p<0·0001 compared with Cal09), along with improvements in seroconversion (24 of 126 [19%, 13·2–26·8]; p=0·011) and influenza-specific CD4+ T-cell responses (73 of 111 [66%, 60·0–75·6; p=0·00028]). The improvement in pH1N1 seroconversion with NY15 was even greater in children who were seronegative at baseline (24 of 64 children [38%, 95% CI 26·7–49·8] vs six of 79 children with Cal09 [8%, 2·8–15·8]; p<0·0001). Persistent shedding to day 7 was independently associated with both seroconversion (odds ratio 12·69, 95% CI 4·1–43·6; p<0·0001) and CD4+ T-cell responses (odds ratio 7·83, 95% CI 2·99–23·5; p<0·0001) by multivariable logistic regression.InterpretationThe pH1N1 component switch that took place between 2016 and 2018 might have overcome the poor efficacy and effectiveness reported with previous LAIV formulations. LAIV effectiveness against pH1N1 should, therefore, improve in upcoming influenza seasons. Our data highlight the importance of assessing replicative fitness, in addition to antigenicity, when selecting annual LAIV components.FundingThe Wellcome Trust.

Development of a Stable Liquid Formulation for Live Attenuated Influenza Vaccine

Live attenuated influenza vaccine (LAIV) is considered one of the most effective vaccines and can be manufactured quickly and inexpensively to counter seasonal or pandemic influenza. Lyophilization is widely used in vaccine production. However, it requires a longer production cycle and large-scale equipment, thus posing a considerable financial burden for developing countries. A potential solution is the development of liquid LAIV, which can increase the yield and reduce the cost of production. In this study, influential factors of LAIV, such as potential stabilizing excipients and pH, were optimized by an orthogonal design. We found that pH is the most critical factor for the stability of LAIV; salt concentration and initial virus titer are also important for LAIV stability. With these data, we developed a liquid formulation consisting of 2.5% sucrose, 0.1% monosodium glutamate, 1% arginine, and 0.5% human serum albumin, with pH ranging from 6.2 to 6.9 (optimum pH 6.5-6.7), for optimal production of monovalent or trivalent LAIVs. This liquid formulation has the potential to considerably improve vaccine production capacity to compensate for the immense shortfall in influenza vaccines globally.

Rationale for vaccination with trivalent or quadrivalent live attenuated influenza vaccines: Protective vaccine efficacy in the ferret model.

Background and aimThe majority of seasonal influenza vaccines are trivalent, containing two A virus strains (H1N1 and H3N2) and one B virus strain. The co-circulation of two distinct lineages of B viruses can lead to mismatch between the influenza B virus strain recommended for the trivalent seasonal vaccine and the circulating B virus. This has led some manufacturers to produce quadrivalent influenza vaccines containing one strain from each B lineage in addition to H1N1 and H3N2 strains. However, it is also important to know whether vaccines containing a single influenza B strain can provide cross-protectivity against viruses of the antigenically distinct lineage. The aim of this study was to assess in naïve ferrets the potential cross-protective activity of trivalent live attenuated influenza vaccine (T-LAIV) against challenge with a heterologous wild-type influenza B virus belonging to the genetically different lineage and to compare this activity with effectiveness of quadrivalent LAIV (Q-LAIV) in the ferret model.Methods and resultsFerrets were vaccinated with either one dose of trivalent LAIV containing B/Victoria or B/Yamagata lineage virus, or quadrivalent LAIV (containing both B lineages), or placebo. They were then challenged with B/Victoria or B/Yamagata lineage wild-type virus 28 days after vaccination. The ferrets were monitored for clinical signs and morbidity. Nasal swabs and lung tissue samples were analyzed for the presence of challenge virus. Antibody response to vaccination was assessed by routine hemagglutination inhibition assay. All LAIVs tested were found to be safe and effective against wild-type influenza B viruses based on clinical signs, and virological and histological data. The absence of interference between vaccine strains in trivalent and quadrivalent vaccine formulations was confirmed. Trivalent LAIVs were shown to have the potential to be cross-protective against infection with genetically different influenza B/Victoria and B/Yamagata lineages.ConclusionsIn this ferret model, quadrivalent vaccine provided higher protection to challenge against both B/Victoria and B/Yamagata lineage viruses. However, T-LAIV provided some cross-protection in the case of a mismatch between circulating and vaccine type B strains. Notably, B/Victoria-based T-LAIV was more protective compared to B/Yamagata-based T-LAIV.

Evaluation of the safety of live attenuated influenza vaccine (LAIV) in children and adolescents with asthma and high-risk conditions: a population-based prospective cohort study conducted in England with the Clinical Practice Research Datalink

ObjectivesTo assess the safety of live attenuated influenza vaccine (LAIV) in children in high-risk groups.DesignNon-interventional cohort study.SettingEngland during 2013–2014 and 2014–2015 influenza seasons.ParticipantsLAIV recipients identified from the Clinical Practice Research...

1663. Marked Improvement in Pandemic H1N1 Component Shedding and Immunogenicity in 2017–2018 Russian-Backbone Live Attenuated Influenza Vaccine (LAIV) in Gambian Children

BackgroundRecent observational studies in the United States have reported reduced effectiveness of the Ann Arbor-backbone live attenuated influenza vaccine (LAIV), coinciding with emergence of 2009 pandemic H1N1 (pH1N1). A recent RCT in Senegal of the Russian-backbone LAIV also showed no efficacy, with pH1N1 the predominant vaccine-matched strain circulating during the study. The reasons for this reduced effectiveness and efficacy are unclear but may involve pre-existing immunity or pH1N1 virus-specific factors. We explore these underlying reasons through an LAIV immunogenicity study in Gambian children across 2 influenza seasons.MethodsGambian children aged 24–59 months (n = 118) were given 2016–17 northern hemisphere Russian-backbone trivalent LAIV. Vaccine shedding, haemagglutinin inhibition (HAI) titre, influenza-specific T-cell responses, and mucosal IgA were measured using RT-PCR, HAI assay, flow cytometry, and ELISA, respectively. The following year, a further 127 children were given 2017–2018 formulation LAIV, where the pH1N1 strain was updated.ResultsIn 2016–2017, significantly less pH1N1 shedding (13.6% children) was seen compared with H3N2 (45.8%) and B/Victoria (80.5%). Similarly, poor pH1N1-specific HAI (5.1% seroconversion), mucosal IgA (18.6% responders) and T-cell responses (<10% responses to pH1N1 HA) were seen, whereas significantly greater responses in ≥1 immune compartments were seen to H3N2 and B/Victoria. pH1N1 shedding was not related to pre-existing immunity in 2016–2017. Vaccination with 2017–2018 LAIV showed improvement in pH1N1 shedding with no significant difference between strains: 67.7%, 63.2%, and 68.4% children shedding pH1N1, H3N2, and B/Victoria at day 2 post-LAIV (see Figure 1). This was matched by enhanced pH1N1 HA-specific T-cell responses, with 47.1% children showing a CD4+IFNg+ and 54.4% a CD4+IL2+ response (see Figure 2). HAI and mucosal IgA data for 2017–2018 are currently being generated and will be presented, as well as key interactions between the parameters measured.ConclusionOur data suggest that poor pH1N1 A/California strain replication in vivo may explain recent suboptimal LAIV performance and suggest that an improvement can be expected with new pH1N1 strains included in current LAIV formulations. Disclosures All authors: No reported disclosures.

The safety of live attenuated influenza vaccine in children and adolescents 2 through 17years of age: A Vaccine Safety Datalink study.

To evaluate the safety of live attenuated influenza vaccine (LAIV) in children 2 through 17years of age. The study was conducted in 6 large integrated health care organizations participating in the Vaccine Safety Datalink (VSD). Trivalent LAIV safety was assessed in children who received LAIV between September 1, 2003 and March 31, 2013. Eighteen pre-specified adverse event groups were studied, including allergic, autoimmune, neurologic, respiratory, and infectious conditions. Incident rate ratios (IRRs) were calculated for each adverse event, using self-controlled case series analyses. For adverse events with a statistically significant increase in risk, or an IRR>2.0 regardless of statistical significance, manual medical record review was performed to confirm case status. During the study period, 396173 children received 590018 doses of LAIV. For 13 adverse event groups, there was no significant increased risk of adverse events following LAIV. Five adverse event groups (anaphylaxis, syncope, Stevens-Johnson syndrome, adverse effect of drug, and respiratory failure) met criteria for manual medical record review. After review to confirm cases, 2 adverse event groups remained significantly associated with LAIV: anaphylaxis and syncope. One confirmed case of anaphylaxis was observed following LAIV, a rate of 1.7 per million LAIV doses. Five confirmed cases of syncope were observed, a rate of 8.5 per million doses. In a study of trivalent LAIV safety in a large cohort of children, few serious adverse events were detected. Anaphylaxis and syncope occurred following LAIV, although rarely. These data provide reassurance regarding continued LAIV use.