Hemagglutination Inhibition Antibody Titers Research Articles

Development and Evaluation of a Novel Chimeric Genotype VII Newcastle Disease Vaccine: Overcoming Maternal Antibody Interference and Spray Administration.

Newcastle disease virus (NDV) poses a significant threat to the poultry industry, with the emergence of genotype VII NDV leading to extensive outbreaks and economic losses. Vaccination is the primary means of controlling NDV, but the presence of maternal antibodies (MDAs) can interfere with the immunological effect of live virus vaccines. Thus, we constructed a chimeric NDV live virus vaccine, LX-OAI4S, by replacing the extracellular regions of the F and HN genes of the NDV LX strain with the corresponding regions of the A-VII vaccine strain. The chimeric vaccine LX-OAI4S demonstrated high genetic stability, good safety, and strong reproductive capacity in chicken embryos. The LX-OAI4S vaccine induced rapid antibody production in specific pathogen-free (SPF) and commercial chickens via the intranasal and intraocular (IN/IO) routes, with hemagglutination inhibition (HI) antibody titers reaching 4.71 ± 1.03 log2 at 7 days post-vaccination (dpv), significantly higher than those of the two classical vaccine strains La Sota and VG/GA. The LX-OAI4S vaccine group provided effective protection against the challenge of genotype VII NDV virulent strain JS2/06 and inhibited viral shedding. When administered via spray, the LX-OAI4S vaccine elicited high systemic immunity against NDV in both SPF and commercial chickens, effectively protecting against clinical disease and reducing viral shedding. The chickens were exposed to high-dose vaccine for spray vaccination, and no adverse reactions were observed after vaccination. Despite the presence of anti-NDV MDAs in chickens, the NDV-specific antibody titers were significantly greater in the vaccinated groups than in the unvaccinated group. The vaccine exhibited high immunogenicity and the potential to overcome maternal antibody interference. The LX-OAI4S vaccine is a promising candidate for an ND vaccine. Its administration via spray can effectively prevent the occurrence of ND, making it a valuable tool for the poultry industry.

Recombinant avian-derived antiviral proteins cIFITM1, cIFITM3, and cViperin as effective adjuvants in inactivated H9N2 subtype avian influenza vaccines

Vaccine adjuvants, serving as non-specific immune enhancers, play a pivotal role in the immunoprevention and control of animal diseases. This study utilized prokaryotic expression systems to express and purify chicken-derived cIFITM1, cIFITM3, and cViperin, which were then formulated as adjuvants with H9N2 avian influenza virus antigens to create inactivated vaccines. These vaccines were administered to SPF chickens to investigate their immunopotentiating functions. Additionally, the proteins were assessed for their ability to act as standalone immune enhancers. The results demonstrated that cIFITM1, cIFITM3, and cViperin significantly elevated serum hemagglutination inhibition (HI) antibody titers. Notably, when used individually, these proteins markedly enhanced the antiviral capabilities of challenged chickens, leading to alleviated clinical symptoms, reduced tracheal virus replication, diminished virus shedding, and lessened histopathological damage, with cIFITM1 exhibiting the most pronounced effect. Furthermore, the protective efficacy of two H9N2 recombinant virus inactivated vaccines supplemented with cIFITM1 adjuvant was validated, achieving a 100 % vaccine protection efficiency. In conclusion, cIFITM1, cIFITM3, and cViperin as adjuvants for influenza vaccines effectively inhibit virus replication and shedding, highlighting their significant potential in influenza prevention and control.

Randomised immunogenicity trial comparing 2019-2020 recombinant and egg-based influenza vaccines among frequently vaccinated healthcare personnel in Israel

ObjectivesTrivalent inactivated influenza vaccine effectiveness was low in a prospective cohort of healthcare personnel (HCP) in Israel from 2016 to 2019. We conducted a randomised immunogenicity trial of quadrivalent recombinant influenza vaccine (RIV4) and standard-dose inactivated influenza vaccine (IIV4) among frequently and infrequently vaccinated previous cohort participants. MethodsFrom October 2019 to January 2020, we enrolled and randomly allocated HCP from two Israeli hospitals to receive IIV4 or RIV4. Hemagglutination inhibition (HAI) antibody titres against 2019-2020 vaccine reference influenza viruses were compared between vaccine groups using geometric mean titre (GMT) ratios from sera collected one-month post-vaccination and by frequency of vaccination in the past 5 years (>2 vs ≤2). ResultsAmong 415 HCP, the GMT ratio comparing RIV4 to IIV4 was 2.0 (95% confidence interval [CI] 1.7-2.7) for A(H1N1)pdm09, 1.6 (95% CI: 1.3-1.9) for A(H3N2), 1.8 (95% CI: 1.4-2.2) for B(Yamagata), and 1.1 (95% CI: 0.9-1.4) for B(Victoria). Similarly, RIV4 elicited higher HAI titres than IIV4 against all 2019-2020 vaccine reference viruses except B(Victoria) among infrequently and frequently vaccinated HCP (lower bound of GMT ratio 95% CIs ≥1.0). ConclusionRIV4 had improved immunogenicity for influenza vaccine strains among both infrequent and frequent vaccinees compared to standard-dose IIV4. Clinical trials registrationNCT04523324

Assessment of PPMV-1 Genotype VI Virulence in Pigeons and Chickens and Protective Effectiveness of Paramyxovirus Vaccines in Pigeons.

Pigeon paramyxovirus serotype 1 (PPMV-1), an antigenic and host variant of avian paramyxovirus Newcastle disease virus (NDV), primarily originating from racing pigeons, has become a global panzootic. Egypt uses both inactivated PPMV-1 and conventional NDV vaccines to protect pigeons from disease and mortality. However, the impact of prevalent strains and the effectiveness of available vaccines in pigeons in Egypt are unclear. This study investigates the virulence of PPMV-1 (Pigeon/Egypt/Sharkia-19/2015/KX580988) and evaluates available paramyxovirus vaccines in protecting pigeons against a PPMV-1 challenge. Ten-day-old specific-pathogen-free (SPF) embryonated chicken eggs infected with this strain exhibited a mean death time (MDT) of 86.4 ± 5.88 h. The intracerebral pathogenicity index (ICPI) in day-old chickens was 0.8, while pigeons experienced an ICPI of 0.96 and an intravenous pathogenicity index (IVPI) of 2.11. These findings classify the strain as virulent and velogenic. Experimental infection of pigeons with this PPMV-1 strain at 106 EID50/0.1 mL resulted in a 62.5% mortality rate, displaying nervous and enteric distress. The virus caused extensive lesions in visceral organs, with strong immunohistochemistry signals in all examined organs, indicating the systemic spread of the virus concurrent to its neurotropic and viscerotropic tropism. Furthermore, vaccination using an inactivated PPMV-1 and live NDV LaSota vaccine regimen protected 100% of pigeons against mortality, while with a single NDV LaSota vaccine, it was 62.5%. The PPMV alone or combined with NDV LaSota induced protective levels of haemagglutination inhibition (HI) antibody titres and reduced virus shedding from buccal and cloacal cavities. Based on generalised linear gamma model analysis, both PPMV-1 and NDV LaSota are antigenically comparable by HI. These findings suggest that using both inactivated PPMV-1 (G-VI) and live attenuated NDV (LaSota) vaccines is an effective prophylactic regimen for preventing and controlling PPMV-1 and NDV in pigeons, thereby reducing the risk of interspecies transmission.

Recombinant Marek’s disease virus type 1 provides full protection against H9N2 influenza A virus in chickens

The H9N2 subtype of the avian influenza virus (AIV) poses a significant threat to the poultry industry and human health. Recombinant vaccines are the preferred method of controlling H9N2 AIV, and Marek’s disease virus (MDV) is the ideal vector for recombinant vaccines. During this study, we constructed two recombinant MDV type 1 strains that carry the hemagglutinin (HA) gene of AIV to provide dual protection against both AIV and MDV. To assess the effects of different MDV insertion sites on the protective efficacy of H9N2 AIV, the HA gene of H9N2 AIV was inserted in UL41 and US2 of the MDV type 1 vector backbone to obtain recombinant viruses rMDV-UL41/HA and rMDV-US2/HA, respectively. An indirect immunofluorescence assay showed sustained expression of HA protein in both recombinant viruses. Additionally, the insertion of the HA gene in UL41 and US2 did not affect MDV replication in cell cultures. After immunization of specific pathogen-free chickens, although both the rMDV-UL41/HA and rMDV-US2/HA groups exhibited similar levels of hemagglutination inhibition antibody titers, only the rMDV-UL41/HA group provided complete protection against the H9N2 AIV challenge, and also offered complete protection against challenge with MDV. These results demonstrated that rMDV-UL41/HA could be used as a promising bivalent vaccine strain against both H9N2 avian influenza and Marek’s disease in chickens.

Immunogenicity and Safety of a Quadrivalent Influenza Vaccine in Population Aged 3 Years and Older in Chile and the Philippines: A Phase 3, Non-Inferiority, Double-Blind, Randomized Controlled Clinical Trial.

In this study, we aimed to evaluate the non-inferiority of a quadrivalent influenza vaccine (QIV) developed by Sinovac Biotech Co., Ltd. (Sinovac, Beijing, China) by comparing its immunogenicity and safety with a comparator QIV (Vaxigrip Tetra®) in a population aged 3 years and older in Chile and the Philippines. A phase 3, non-inferiority, double-blind, randomized controlled, multicenter clinical trial was conducted in the southern hemisphere (SH) 2023 influenza season. Participants aged ≥ 3 years old with stable health were randomized 1:1 to receive either Sinovac QIV or comparator QIV. The co-primary outcomes were immunological non-inferiority for Sinovac QIV versus the comparator against each strain contained in the vaccines in terms of seroconversion rates (SCRs) and geometric mean titers (GMTs) of hemagglutination inhibition (HI) antibodies 28 days after final vaccination. A total of 2039 participants were vaccinated (1019 Sinovac QIV; 1020 comparator QIV). Sinovac QIV induced non-inferior immune responses to all four strains as compared to comparator QIV, with slightly higher GMTs than those of comparator QIV: GMT ratios (lower limit 95% confidence interval (CI)) were 1.8 (1.6) for A(H1N1), 1.4 (1.3) for A (H3N2), 1.3 (1.1) for B Victoria and 1.2 (1.1) for B Yamagata; observed seroconversion rate differences (lower limit 95% CI) were 9.6% (6.7) for A(H1N1), 7.0% (3.5) for A(H3N2), 2.4% (-0.03) for B Victoria and 6.8% (3.0) for B Yamagata. Adverse reactions were similar across the two groups and no vaccine-related serious adverse events were reported. The immunogenicity of Sinovac QIV was non-inferior to that of the comparator QIV in these populations aged 3 years and older, and safety was comparable.

Recombinant Hemagglutinin Protein from H9N2 Avian Influenza Virus Exerts Good Immune Effects in Mice.

The H9N2 subtype of avian influenza virus (AIV) causes enormous economic losses and poses a significant threat to public health; the development of vaccines against avian influenza is ongoing. To study the immunogenicity of hemagglutinin (HA) protein, we constructed a recombinant pET-32a-HA plasmid, induced HA protein expression with isopropyl β-D-1-thiogalactopyranoside (IPTG), verified it by SDS-PAGE and Western blotting, and determined the sensitivity of the recombinant protein to acid and heat. Subsequently, mice were immunized with the purified HA protein, and the immunization effect was evaluated according to the hemagglutination inhibition (HI) titer, serum IgG antibody titer, and cytokine secretion level of the mice. The results showed that the molecular weight of the HA protein was approximately 84 kDa, and the protein existed in both soluble and insoluble forms; in addition, the HA protein exhibited good acid and thermal stability, the HI antibody titer reached 6 log2-8 log2, and the IgG-binding antibody titer was 1:1,000,000. Moreover, the levels of IL-2, IL-4, and IL-5 in the immunized mouse spleen cells were significantly increased compared with those in the control group. However, the levels of IL-1β, IL-6, IL-13, IFN-γ, IL-18, TNF-α, and GM-CSF were decreased in the immunized group. The recombinant HA protein utilized in this study exhibited good stability and exerted beneficial immune effects, providing a theoretical basis for further research on influenza vaccines.

THE USE OF EMBRYONATED CHICKEN EGGS WITH MATERNAL ANTIBODY TO NEWCASTLE DISEASE VIRUS FOR THE PRODUCTION OF LA SOTA STRAIN VIRAL ANTIGEN

Embryonated eggs from Specific Pathogen Free (SPF) flocks are used ideally in the production of Newcastle disease vaccine. However, in developing countries where SPF flocks are not available, embryonated eggs from healthy chicken flocks are utilized. The present study assessed the use of embryonated eggs having maternal antibodies to Newcastle disease virus (NDV) for the propagation of NDV La Sota vaccine strain. Log, hemagglutination inhibition (HI) antibody titers to NDV in sera of 18 Isa White breeder chickens were determined. Subsequently within one week, 60 eggs were collected from the breeder hens and incubated for 12 days. Maternal antibodies to NDV in the 12-day-old embrayonated eggs were determined from the egg yolk and allantoic fluid. Two fertile eggs each from five hens were then inoculated with 0.1 or 0.2 mL of La Sota vaccine reconstituted in PBS with pH of 7.4 (200 doses/mL). In addition, three eggs from different hens were inoculated with 0.1 mL of the La Sota vaccine. Log: hemagglutination (HA) NDV titers in allantoic fluid were determined from the eggs three days post inoculation. The geometric mean of HI log, antibody titers to NDV detected in sera, yolk and allantoic fluid of eggs were, 7.37, 7.09 and 1.93, respectively. There was no statistically significant difference (p 0.05) between NDV HA log: titers in allantoic fluid harvested following inoculation with 0.1 (between 9 log: to 11 log:) and 0.2 (between 8 log: to 12 log:) mL La Sota vaccine. There was no correlation (r=-0.28) between antibodies to NDV in sera of breeders and the viral titers obtained in allantoic fluid of their embryonated eggs post inoculation with La Sota vaccine. The results of this study indicate that embryonated eggs with maternal antibodies to NDV could be used for propagation of NDV to yield high viral titers. Hence, it is recommended that breeder flocks raised for the purpose of producing eggs intended for NDV vaccine production could be duly vaccinated against field NDV infection.

Isolation and characterization of porcine parvovirus in Vietnam.

No study has successfully isolated parvovirus in Vietnam. This study aimed to isolate and characterize parvovirus strains indigenous in Vietnam for vaccine development against porcine parvovirus (PPV). We collected serum and stillbirth samples from six provinces in Vietnam, and PPV-positive samples were identified using a polymerase chain reaction. Parvovirus isolation was attempted using the PK-15 cells maintained in a minimum essential medium supplemented with 5% fetal bovine serum and 1% antibiotics (Penicillin-streptomycin). The cells were incubated at 37°C with 5% CO2. Virulence experiments were conducted on white primiparous sows to evaluate the virulence of the PPV strain through hemagglutination inhibition (HI) titers and fetus lesions. We analyzed 360 serum and 32 stillbirth (liver and lungs) samples, revealing that 32/392 (8.2% ) of them were PPV-positive, all belonging to PPV1. Thirty-two PPV-positive samples were successfully isolated, with 100% identity as VP2 sequences. The phylogenetic tree revealed a close relationship with the Kresse strain (isolated from Canada in 1996) and the PPV1-0225-L-SD strain (isolated from China in 2022). Two PPV isolates (VC5 from Dongnai and TX7 from Thanhhoa) that exhibited high 50% tissue culture infectious dose titers were selected for the virulence experiment. On day 21, after injection, the HI antibody titers ranged from 10log2 to 12log2. On day 90, 71%-80% of fetuses were mummified. This study showed that the PPV infection rate in Vietnam was 8.2%. Thirty-two isolates belonged to PPV1. Two PPV strains, VC5 and TX7, were determined to be highly virulent by the results of HI titers after injection into gilts. VC5 and TX7 were determined to be good candidates for further research on PPV vaccines.

An avian-origin internal backbone effectively increases the H5 subtype avian influenza vaccine candidate yield in both chicken embryonated eggs and MDCK cells

Inactivated vaccines play an important role in preventing and controlling the epidemic caused by the H5 subtype avian influenza virus. The vaccine strains are updated in response to alterations in surface protein antigens, while an avian-derived vaccine internal backbone with a high replicative capacity in chicken embryonated eggs and MDCK cells is essential for vaccine development. In this study, we constructed recombinant viruses using the clade 2.3.4.4d A/chicken/Jiangsu/GY5/2017(H5N6, CkG) strain as the surface protein donor and the clade 2.3.4.4b A/duck/Jiangsu/84512/2017(H5N6, Dk8) strain with high replicative ability as an internal donor. After optimization, the integration of the M gene from the CkG into the internal genes from Dk8 (8GM) was selected as the high-yield vaccine internal backbone, as the combination improved the hemagglutinin1/nucleoprotein (HA1/NP) ratio in recombinant viruses. The r8GMΔG with attenuated hemagglutinin and neuraminidase from the CkG exhibited high-growth capacity in both chicken embryos and MDCK cell cultures. The inactivated r8GMΔG vaccine candidate also induced a higher hemagglutination inhibition antibody titer and microneutralization titer than the vaccine strain using PR8 as the internal backbone. Further, the inactivated r8GMΔG vaccine candidate provided complete protection against wild-type strain challenge. Therefore, our study provides a high-yield, easy-to-cultivate candidate donor as an internal gene backbone for vaccine development.

Insect Cell-Based Quadrivalent Seasonal Influenza Virus-like Particles Vaccine Elicits Potent Immune Responses in Mice.

Influenza viruses can cause highly infectious respiratory diseases, posing noteworthy epidemic and pandemic threats. Vaccination is the most cost-effective intervention to prevent influenza and its complications. However, reliance on embryonic chicken eggs for commercial influenza vaccine production presents potential risks, including reductions in efficacy due to HA gene mutations and supply delays due to scalability challenges. Thus, alternative platforms are needed urgently to replace egg-based methods and efficiently meet the increasing demand for vaccines. In this study, we employed a baculovirus expression vector system to engineer HA, NA, and M1 genes from seasonal influenza strains A/H1N1, A/H3N2, B/Yamagata, and B/Victoria, generating virus-like particle (VLP) vaccine antigens, H1N1-VLP, H3N2-VLP, Yamagata-VLP, and Victoria-VLP. We then assessed their functional and antigenic characteristics, including hemagglutination assay, protein composition, morphology, stability, and immunogenicity. We found that recombinant VLPs displayed functional activity, resembling influenza virions in morphology and size while maintaining structural integrity. Comparative immunogenicity assessments in mice showed that our quadrivalent VLPs were consistent in inducing hemagglutination inhibition and neutralizing antibody titers against homologous viruses compared to both commercial recombinant HA and egg-based vaccines (Vaxigrip). The findings highlight insect cell-based VLP vaccines as promising candidates for quadrivalent seasonal influenza vaccines. Further studies are worth conducting.

Differential Regulation of DC Function, Adaptive Immunity, and MyD88 Dependence by MF59 and AS03-like Adjuvants.

MF59 and AS03 are squalene emulsion-based vaccine adjuvants with similar compositions and droplet sizes. Despite their broad use in licensed influenza vaccines, few studies compared their adjuvant effects and action mechanisms side by side. Considering the majority of adjuvants act on dendritic cells (DCs) to achieve their adjuvant effects, this study compared MF59 and AS03-like adjuvants (AddaVax and AddaS03, respectively) to enhance antigen uptake, DC maturation, ovalbumin (OVA) and seasonal influenza vaccine-induced immune responses. Considering MF59 was reported to activate MyD88 to mediate its adjuvant effects, this study also investigated whether the above-explored adjuvant effects of AddaVax and AddaS03 depended on MyD88. We found AddaVax more potently enhanced antigen uptake at the local injection site, while AddaS03 more potently enhanced antigen uptake in the draining lymph nodes. AddaS03 but not AddaVax stimulated DC maturation. Adjuvant-enhanced antigen uptake was MyD88 independent, while AddaS03-induced DC maturation was MyD88 dependent. AddaVax and AddaS03 similarly enhanced OVA-induced IgG and subtype IgG1 antibody responses as well as influenza vaccine-induced hemagglutination inhibition antibody titers, whileAddaS03 more potently enhanced OVA-specific IgG2c antibody responses. Both adjuvants depended on MyD88 to enhance vaccine-induced antibody responses, while AddaVax depended more on MyD88 to achieve its adjuvant effects. Our study reveals similarities and differences of the two squalene emulsion-based vaccine adjuvants, contributing to our improved understanding of their action mechanisms.

Sex Differences in the Immunogenicity and Efficacy of Seasonal Influenza Vaccines: A Meta-analysis of Randomized Controlled Trials.

Sex impacts individuals' response to vaccination. However, most vaccine studies do not report these differences disaggregated by sex. The aim of this study was to assess sex differences in the immunogenicity and efficacy of influenza vaccine. We performed a meta-analysis using phase 3 randomized controlled trial data conducted between 2010 and 2018. Using hemagglutination inhibition antibody titers for each strain, differences in geometric mean ratios (GMRs) were calculated by sex. Risk ratios (RRs) comparing seroconversion proportions were pooled for females and males using random-effects models. Vaccine efficacy (VE) was assessed. Data were analyzed by age group (18-64 vs ≥65 years). A total of 33 092 healthy adults from 19 studies were included for immunogenicity analysis, and 6740 from 1 study for VE. Whereas no sex differences in immunogenicity were found in adults <65 years old, older females had a significantly greater chance to seroconvert compared to older males for all strains: RRH1N1 = 1.17 [95% confidence interval {CI}, 1.12-1.23]; RRH3N2 = 1.09 [95% CI, 1.05-1.14]; RRVictoria = 1.23 [95% CI, 1.14-1.31]; RRYamagata = 1.22 [95% CI, 1.14-1.30]. GMRs were also higher in older females for all strains compared to older males. VE in preventing laboratory-confirmed influenza was higher in older females compared to older males with VEs of 27.32% (95% CI, 1.15%-46.56%) and 6.06% (95% CI, -37.68% to 35.90%), respectively. Our results suggest a higher immunogenicity and VE in females compared to males in older adults. These differences in immunogenicity and VE support the disaggregation of vaccine data by sex in clinical trials and observational studies. CRD42018112260.

Evaluation of the Newcastle disease virus genotype VII–mismatched vaccines in SPF chickens: A challenge efficacy study

Newcastle disease virus (NDV) strains, while falling under a single serotype, are classified into distinct genotypes. Genotype VII virulent NDVs pose a significant threat to poultry due to their association with high mortality rates and economic losses. This study aimed to evaluate the efficacy of three commercial live vaccines based on genotype II against genotype VII virulent NDV (vNDV) in specific pathogen-free (SPF) chickens. Forty one-day-old chickens were randomly divided into four groups (n = 10) and inoculated with one dose of each ND pneumotropic vaccine—B1, Clone.12IR, and La Sota—or received phosphate-buffered saline (PBS) as a control at eight days of age via eye drop. At 28 days of age (20th post-vaccination days), chickens were intramuscularly challenged with genotype VII virulent NDV (≥ 105 LD50). Serum samples were collected at 28 days of age (challenge day), 7 and 14 post-challenge days to measure NDV antibodies via the hemagglutination inhibition (HI) test. Cloacal and oropharyngeal swabs were taken on the 3rd, 5th, 7th, and 10th post-challenge days to evaluate virus shedding. Vaccinated groups exhibited significantly higher antibody titers and greater protection levels compared to the control group (P≤ 0.001). While HI antibody titer was not different at 28 and 35 days of age between vaccinated chickens, the Clone.12IR groups showed higher HI antibody titer compared to B1 at day 42 of age (9.43 vs. 7.42; P≤ 0.002). La Sota and Clone.12IR vaccines demonstrated superior protection against mortality compared to the B1 vaccine (90 %, 80% vs. 60 %, respectively) with 6.0 and 2.67 odds ratio of survivability. All three mismatched vaccines effectively curbed the shedding of virulent genotype VII NDV, with 0 % to 11 % positive cloacal samples up to the 3rd post-challenge day. These findings demonstrate that in the experimental setting, the administration of mismatched ND vaccines, particularly La Sota and Clone.12IR, confer protection against genotype VII virulent NDV and control viral shedding, which can help to develop effective vaccination strategies to mitigate the impact of vNDV outbreaks in the poultry farms.

A Phase 2 Clinical Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of Different Prime-Boost Vaccination Schedules of 2013 and 2017 A(H7N9) Inactivated Influenza Virus Vaccines Administered With and Without AS03 Adjuvant in Healthy US Adults.

A surge of human influenza A(H7N9) cases began in 2016 in China from an antigenically distinct lineage. Data are needed about the safety and immunogenicity of 2013 and 2017 A(H7N9) inactivated influenza vaccines (IIVs) and the effects of AS03 adjuvant, prime-boost interval, and priming effects of 2013 and 2017 A(H7N9) IIVs. Healthy adults (n = 180), ages 19-50 years, were enrolled into this partially blinded, randomized, multicenter phase 2 clinical trial. Participants were randomly assigned to 1 of 6 vaccination groups evaluating homologous versus heterologous prime-boost strategies with 2 different boost intervals (21 vs 120 days) and 2 dosages (3.75 or 15 μg of hemagglutinin) administered with or without AS03 adjuvant. Reactogenicity, safety, and immunogenicity measured by hemagglutination inhibition and neutralizing antibody titers were assessed. Two doses of A(H7N9) IIV were well tolerated, and no safety issues were identified. Although most participants had injection site and systemic reactogenicity, these symptoms were mostly mild to moderate in severity; injection site reactogenicity was greater in vaccination groups receiving adjuvant. Immune responses were greater after an adjuvanted second dose, and with a longer interval between prime and boost. The highest hemagglutination inhibition geometric mean titer (95% confidence interval) observed against the 2017 A(H7N9) strain was 133.4 (83.6-212.6) among participants who received homologous, adjuvanted 3.75 µg + AS03/2017 doses with delayed boost interval. Administering AS03 adjuvant with the second H7N9 IIV dose and extending the boost interval to 4 months resulted in higher peak antibody responses. These observations can broadly inform strategic approaches for pandemic preparedness. Clinical Trials Registration. NCT03589807.

Hemagglutination Inhibition Antibody Titers as Mediators of Influenza Vaccine Efficacy Against Symptomatic Influenza A(H1N1), A(H3N2), and B/Victoria Virus Infections.

The hemagglutination inhibition antibody (HAI) titer contributes only a part of vaccine-induced protection against influenza virus infections. Using causal mediation analysis, we quantified the proportion of vaccine efficacy mediated by postvaccination HAI titers. We conducted causal mediation analyses using data from a randomized, active-comparator controlled, phase III, trial of an inactivated, split-virion seasonal quadrivalent influenza vaccine in children conducted from October 2010 to December 2011 in 8 countries. Vaccine efficacy was estimated using a weighted Cox proportional hazards model. Estimates were decomposed into the direct and indirect effects mediated by postvaccination HAI titers. The proportions of vaccine efficacy mediated by postvaccination HAI titers were estimated to be 22% (95% confidence interval, 18%--47%) for influenza A(H1N1), 20% (16%-39%) for influenza A(H3N2), and 37% (26%-85%) for influenza B/Victoria. HAI titers partially mediate influenza vaccine efficacy against influenza A(H1N1), A(H3N2), and B/Victoria. Our estimates were lower than in previous studies, possibly reflecting expected heterogeneity in antigenic similarity between vaccine and circulating viruses across seasons.

Immunophenotypic predictors of influenza vaccine immunogenicity in pediatric hematopoietic cell transplant recipients

AbstractPediatric hematopoietic cell transplant (HCT) recipients exhibit poor serologic responses to influenza vaccination early after transplant. To facilitate the optimization of influenza vaccination timing, we sought to identify B- and T-cell subpopulations associated with influenza vaccine immunogenicity in this population. We used mass cytometry to phenotype peripheral blood mononuclear cells collected from pediatric HCT recipients enrolled in a multicenter influenza vaccine trial comparing high- and standard-dose formulations over 3 influenza seasons (2016-2019). We fit linear regression models to estimate relationships between immune cell subpopulation numbers before vaccination and prevaccination to postvaccination geometric mean fold rises in antigen-specific (A/H3N2, A/H1N1, and B/Victoria) serum hemagglutination inhibition antibody titers (28-42 days, and ∼6 months after 2 doses). For cell subpopulations identified as predictive of a response to all 3 antigens, we conducted a sensitivity analysis including time after transplant as an additional covariate. Among 156 HCT recipients, we identified 33 distinct immune cell subpopulations; 7 significantly predicted responses to all 3 antigens 28 to 42 days after a 2-dose vaccine series, irrespective of vaccine dose. We also found evidence that baseline absolute numbers of naïve B cells, naïve CD4+ T cells, and circulating T follicular helper cells predicted peak and sustained vaccine-induced titers irrespective of dose or timing of posttransplant vaccine administration. In conclusion, several B- and T-cell subpopulations predicted influenza vaccine immunogenicity in pediatric HCT recipients. This study provides insights into the immune determinants of vaccine responses and may help guide the development of tailored vaccination strategies for this vulnerable population.

Pre-vaccination immunotypes reveal weak and robust antibody responders to influenza vaccination.

Effective vaccine-induced immune responses are particularly essential in older adults who face an increased risk of immunosenescence. However, the complexity and variability of the human immune system make predicting vaccine responsiveness challenging. To address this knowledge gap, our study aimed to characterize immune profiles that are predictive of vaccine responsiveness using "immunotypes" as an innovative approach. We analyzed an extensive set of innate and adaptive immune cell subsets in the whole blood of 307 individuals (aged 25-92) pre- and post-influenza vaccination which we associated with day 28 hemagglutination inhibition (HI) antibody titers. Building on our previous work that stratified individuals into nine immunotypes based on immune cell subsets, we identified two pre-vaccination immunotypes associated with weak and one showing robust day 28 antibody response. Notably, the weak responders demonstrated HLA-DR+ T-cell signatures, while the robust responders displayed a high naïve-to-memory T-cell ratio and percentage of nonclassical monocytes. These specific signatures deepen our understanding of the relationship between the baseline of the immune system and its functional potential. This approach could enhance our ability to identify individuals at risk of immunosenescence. Our findings highlight the potential of pre-vaccination immunotypes as an innovative tool for informing personalized vaccination strategies and improving health outcomes, particularly for aging populations.

Concomitant Administration of Ad26.RSV.preF/RSV preF Protein Vaccine and High-Dose Influenza Vaccine in Adults 65 Years and Older: A Noninferiority Trial.

Since influenza and respiratory syncytial virus (RSV) carry significant burden in older adults with overlapping seasonality, vaccines for both pathogens would ideally be coadministered in this population. Here we evaluate the immunogenicity and safety of concomitant administration of Ad26.RSV.preF/RSV preF protein and high-dose seasonal influenza vaccine (Fluzone-HD) in adults ≥65 years old. Participants were randomized 1:1 to the Coadministration or Control group. The Coadministration group received concomitant Ad26.RSV.preF/RSV preF protein and Fluzone-HD on day 1 and placebo on day 29, while the Control group received Fluzone-HD and placebo on day 1 and Ad26.RSV.preF/RSV preF protein on day 29. Influenza hemagglutination-inhibiting and RSV preF-binding antibody titers were measured postvaccination and tested for noninferiority between both groups. Safety data were collected throughout the study and analyzed descriptively. Coadministered Ad26.RSV.preF/RSV preF protein and Fluzone-HD vaccines induced noninferior immune responses compared to each vaccine administered alone. Seroconversion and seroprotection rates against influenza were similar between groups. Both vaccines remained well tolerated upon concomitant administration. Coadministration of Ad26.RSV.preF/RSV preF protein and Fluzone-HD showed an acceptable safety profile and did not hamper the immunogenicity of either vaccine, thus supporting that both vaccines can be concomitantly administered in adults ≥65 years old.

Household immunity and individual risk of infection with dengue virus in a prospective, longitudinal cohort study.

Although it is known that household infections drive the transmission of dengue virus (DENV), it is unclear how household composition and the immune status of inhabitants affect the individual risk of infection. Most population-based studies to date have focused on paediatric cohorts because more severe forms of dengue mainly occur in children, and the role of adults in dengue transmission is understudied. Here we analysed data from a multigenerational cohort study of 470 households, comprising 2,860 individuals, in Kamphaeng Phet, Thailand, to evaluate risk factors for DENV infection. Using a gradient-boosted regression model trained on annual haemagglutination inhibition antibody titre inputs, we identified 1,049 infections, 90% of which were subclinical. By analysing imputed infections, we found that individual antibody titres, household composition and antibody titres of other members in the same household affect an individual's risk of DENV infection. Those individuals living in households with high average antibody titres, or households with more adults, had a reduced risk of infection. We propose that herd immunity to dengue acts at the household level and may provide insight into the drivers of the recent change in the shifting age distribution of dengue cases in Thailand.