Background Influenza infects 5–15% of the global population each year, and obesity has been shown to be an independent risk factor for increased influenza-related complications including hospitalization and death. However, the risk of developing influenza or ILI in a vaccinated obese adult population has not been addressed. Objective This study evaluated whether obesity was associated with increased risk of influenza and influenza-like illness among vaccinated adults. Subjects and Methods During the 2013–2014 and 2014–2015 influenza seasons, we recruited 1042 subjects to a prospective observational study of trivalent inactivated influenza vaccine (IIV3) in adults.1022 subjects completed the study. Assessments of relative risk for laboratory confirmed influenza and influenza-like illness were determined based on BMI. Seroconversion and seroprotection rates were determined using pre-vaccination and 26–35 days post-vaccination serum samples. Recruitment criteria for this study were adults 18 years of age and older receiving the seasonal trivalent inactivated influenza vaccine (IIV3) for the years 2013–2014 and 2014–2015. Exclusion criteria were immunosuppressive diseases, use of immunomodulatory or immunosuppressive drugs, acute febrile illness, history of Guillain-Barre syndrome, use of theophylline preparations, or use of warfarin. Results Among obese, 9.8% had either confirmed influenza or influenza-like-illness compared with 5.1% of healthy weight participants. Compared with vaccinated healthy weight, obese participants had double the risk of developing influenza or influenza-like illness (relative risk= 2.01, 95% CI 1.12, 3.60, p=0.020). Seroconversion or seroprotection rates were not different between healthy weight and obese adults with influenza or ILI. Conclusions Despite robust serological responses, vaccinated obese adults are twice as likely to develop influenza and influenza-like illness compared to healthy weight adults. This finding challenges the current standard for correlates of protection, suggesting use of antibody titers to determine vaccine effectiveness in an obese population may provide misleading information.

Background Influenza A virus (IAV) infection is a common respiratory tract infection that causes considerable morbidity and mortality worldwide. Objective To investigate the effect of a genetic deficiency of tissue factor (TF) in a mouse model of influenza A infection. Methods Wild-type mice, low tissue factor (LTF) mice and mice with the TF gene deleted in different cell types were infected with a mouse-adapted A/Puerto Rico/8/34 H1N1 strain of IAV. TF expression was measured in the lungs, and bronchoalveolar lavage fluid (BALF) was collected to measure extracellular vesicle TF, activation of coagulation, alveolar hemorrhage and inflammation. Results IAV infection of wild-type mice increased lung TF expression, activation of coagulation and inflammation in the BALF, but also led to alveolar hemorrhage. LTF mice and mice with a selective deficiency of TF in lung epithelial cells had low basal levels of TF and failed to increase TF expression after infection; these two strains of mice had more alveolar hemorrhage and death compared with controls. In contrast, deletion of TF in either myeloid cells or endothelial cells and hematopoietic cells did not increase alveolar hemorrhage or death after IAV infection. These results indicate that TF expression in the lung, particularly in epithelial cells, is required to maintain alveolar hemostasis after IAV infection. Conclusion Our study indicates that TF-dependent activation of coagulation is required to limit alveolar hemorrhage and death after influenza A infection.

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Influenza A virus infection is a common respiratory tract infection. Alveolar hemorrhage has been reported in patients with influenza pneumonia and in mice infected with influenza A. In this study, we investigated the effect of two anticoagulants on alveolar hemorrhage after influenza A virus (IAV) infection of wild‐type mice. Wild‐type mice were anticoagulated with either warfarin or the direct thrombin inhibitor dabigatran etexilate and then infected with a mouse‐adapted influenza virus (A/Puerto Rico/8/34 H1N1). Alveolar hemorrhage was assessed by measuring hemoglobin levels in the bronchoalveolar lavage fluid (BALF). We also measured vascular permeability and viral genomes in the lung, as well as white blood cells, inflammatory mediators, and protein in BALF. Survival and body weight were monitored for 14 days after influenza A infection. In infected mice receiving either warfarin or dabigatran etexilate we observed decreased activation of coagulation in the BALF and increased alveolar hemorrhage. Warfarin but not dabigatran etexilate increased vascular permeability and mortality of influenza A‐infected mice. Anticoagulation did not affect levels of influenza A genomes, white blood cells, inflammatory mediators, or protein in the BALF. Our study indicates that systemic anticoagulation increases alveolar hemorrhage in influenza A‐infected mice.

HIV Vaccine Trials Network (HVTN) 505 was a phase 2b efficacy trial of a DNA/recombinant adenovirus 5 (rAd5) HIV vaccine regimen. Although the trial was stopped early for lack of overall efficacy, later correlates of risk and sieve analyses generated the hypothesis that the DNA/rAd5 vaccine regimen protected some vaccinees from HIV infection yet enhanced HIV infection risk for others. Here, we assessed whether and how host Fc gamma receptor (Fc␥R) genetic variations influenced the DNA/rAd5 vaccine regimen's effect on HIV infection risk. We found that vaccine receipt significantly increased HIV acquisition compared with placebo receipt among participants carrying the FCGR2C-TATA haplotype (comprising minor alleles of four FCGR2C single-nucleotide polymorphism [SNP] sites) (hazard ratio [HR] ϭ 9.79, P ϭ 0.035) but not among participants without the haplotype (HR ϭ 0.86, P ϭ 0.67); the interaction of vaccine and haplotype effect was significant (P ϭ 0.034). Similarly, vaccine receipt increased HIV acquisition compared with placebo receipt among participants carrying the FCGR3B-AGA haplotype (comprising minor alleles of the 3 FCGR3B SNPs) (HR ϭ 2.78, P ϭ 0.058) but not among participants without the haplotype (HR ϭ 0.73, P ϭ 0.44); again, the interaction of vaccine and haplotype was significant (P ϭ 0.047). The FCGR3B-AGA haplotype also influenced whether a combined Env-specific CD8 ϩ T-cell polyfunctionality score and IgG response correlated significantly with HIV risk; an FCGR2A SNP and two FCGR2B SNPs influenced whether anti-gp140 antibody-dependent cellular phagocytosis correlated significantly with HIV risk. These results provide further evidence that Fc gamma receptor genetic variations may modulate HIV vaccine effects and immune function after HIV vaccination.

Adjuvants can alter the magnitude, characteristics, and persistence of the humoral response to protein vaccination. HIV vaccination might benefit from tailored adjuvant choice as raising a durable and protective response to vaccination has been exceptionally challenging. Analysis of trials of partially effective HIV vaccines have identified features of the immune response that correlate with decreased risk, including high titers of V1V2-binding IgG and IgG3 responses with low titers of V1V2-binding IgA responses and enhanced Fc effector functions, notably antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). However, there has been limited opportunity to compare the effect of different adjuvants on these activities in humans. Here, samples from the AVEG015 study, a phase 1 trial in which participants (n = 112) were immunized with gp120SF-2 and one of six different adjuvants or combinations thereof were assessed for antibody titer, biophysical features, and diverse effector functions. Three adjuvants, MF59 + MTP-PE, SAF/2, and SAF/2 + MDP, increased the peak magnitude and durability of antigen-specific IgG3, IgA, FcγR-binding responses and ADCP activity, as compared to alum. While multiple adjuvants increased the titer of IgG, IgG3, and IgA responses, none consistently altered the balance of IgG to IgA or IgG3 to IgA. Linear regression analysis identified biophysical features including gp120-specific IgG and FcγR-binding responses that could predict functional activity, and network analysis identified coordinated aspects of the humoral response. These analyses reveal the ability of adjuvants to drive the character and function of the humoral response despite limitations of small sample size and immune variability in this human clinical trial.

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Vaccination with influenza vaccine is the best method to prevent or lessen infection with influenza virus. While obesity is an independent risk factor for developing severe influenza infection, the efficacy of influenza vaccine in obese humans is an emerging research area. We have previously demonstrated that serum titers of influenza vaccine specific IgG has a steeper decline one year post vaccination in an obese population compared with healthy weight individuals. To determine if subclasses of immunogloblulin (Ig) IgG or total IgM were also impaired in an obese population post influenza vaccination, we assessed the immunoglobulin response to influenza vaccination in adults. Patients visiting the UNC Family Practice Health Center to receive the 2012‐2013 seasonal trivalent influenza vaccine (TIV) were invited to participate in this study. A blood sample was drawn prior to receiving the vaccine, as well as thirty days post vaccination. Height and weight measurements were used to calculate BMI. Using an ELISA, pre and post vaccination serum samples were analyzed for TIV‐specific IgM, IgG1, IgG2, IgG3, IgG4, as well as total IgG. We report here that obesity was associated with a lower IgG1 response post vaccination in 18‐35 year old participants compared with healthy weight and overweight individuals. Participants above the age of 61 had decreased levels of IgM and IgG3, compared to younger participants, regardless of weight status. These data suggest that immunoglobulin subclasses are independently affected by weight status and age and may play a role in the increased susceptibility to severe influenza infection found in obese individuals. Grant Funding Source: Supported by the National Institutes of Health