Decreased ratio of influenza-specific IgG versus IgM in response to influenza vaccination in antiretroviral-treated HIV-infected African Americans compared to Caucasians, and its direct correlation with the percentages of peripheral Tfh cells.
与白种人相比，抗逆转录病毒治疗的 HIV 感染的非洲裔美国人对流感疫苗接种应答的流感特异性 IgG 与 IgM 的比率降低，及其与外周 Tfh 细胞百分比的直接相关性。
- 作者列表："Ma P","Luo Z","Qian J","Yan Z","Zhang L","Martin L","Wang Z","Xia H","Yu F","Jiang W
BACKGROUND:Racial differences have been observed in the rate of bacterial infection and disease progression in HIV. Here, we evaluate racial differences in seasonal influenza vaccine responses. METHODS:16 healthy controls (9 Caucasians (CC) and 7 African Americans (AA)) and 26 antiretroviral therapy (ART)-treated aviremic HIV+ subjects (11 CC and 15 AA) were enrolled in the current study. Blood was collected at pre-vaccination (D0) and day 14 (D14) following seasonal influenza vaccination. Serologic responses were characterized in plasma by ELISA. B and T cells were assessed by flow cytometry ex vivo. RESULTS:The absolute counts of CD4+ CD3+ T cells and CD19+ B cells were similar in healthy controls and HIV-infected individuals, and similar in CC and AA in the two study groups. However, the percentage of peripheral T follicular helper (pTfh) cells was decreased in HIV+ AA compared to HIV+ CC. There were no racial differences in IgG antibody responses against vaccination in the two study groups. However, the ratio of anti-influenza-specific IgG versus IgM induction following vaccination was decreased in HIV+ AA compared to HIV+ CC, which was directly correlated with the percentages of pTfh cells. This racial difference and correlation were not demonstrable in healthy controls. CONCLUSION:Here we report that HIV + AA has decreased fold induction of IgG versus IgM after influenza vaccination, which may suggest impaired class-switching from IgM to IgG in AA HIV-infected individuals.
背景: 在 HIV 的细菌感染率和疾病进展方面已观察到种族差异。在此，我们评估季节性流感疫苗反应的种族差异。 方法: 16 例健康对照 (9 例白种人 (CC) 和 7 例非裔美国人 (AA)) 和 26 例抗逆转录病毒疗法 (ART) 治疗的 aviremic HIV + 受试者 (11 例 CC 和 15 例 AA) 入选本研究。在接种前 (D0) 和接种季节性流感疫苗后第 14 天 (D14) 采集血液。通过 ELISA 在血浆中表征血清学反应。通过流式细胞术离体评估 B 和 T 细胞。 结果: 健康对照组和 HIV 感染者 CD4 + CD3 + T 细胞和 CD19 + b细胞的绝对计数相似，两个研究组 CC 和 AA 的绝对计数相似。然而，与 HIV + CC 相比，HIV + AA 中外周 T 滤泡辅助细胞 (pTfh) 细胞的百分比降低。在两个研究组中，针对疫苗接种的 IgG 抗体反应没有种族差异。然而，与 HIV + CC 相比，HIV + AA 中疫苗接种后抗流感特异性 IgG 与 IgM 诱导的比率降低，这与 pTfh 细胞的百分比直接相关。这种种族差异和相关性在健康对照组中未能证明。 结论: 在这里我们报道了 HIV + AA 在流感疫苗接种后 IgG 与 IgM 的诱导作用降低了 4 倍，这可能提示 AA HIV 感染者从 IgM 到 IgG 的类别转换受损。
METHODS:BACKGROUND:From 2015/16 through 2017/18, injectable, trivalent inactivated influenza vaccines (IIV3) and a nasal spray, tetravalent live-attenuated influenza vaccine (LAIV4) were used in parallel in Finland. To understand how well vaccination with each vaccine type protected children against influenza under real-life conditions, vaccine effectiveness in two-year-olds was estimated for all three seasons. METHODS:Each season, a nationwide register-based cohort study was conducted. The study population comprised 60,088 children in 2015/16, 60,860 children in 2016/17 and 60,345 children in 2017/18. Laboratory-confirmed influenza was the study outcome. Seasonal influenza vaccination with either LAIV4 or IIV3 was the time-dependent exposure of interest. Vaccine effectiveness was defined as 1 minus the hazard ratio comparing vaccinated with unvaccinated children. RESULTS:From 2015/16 through 2017/18, the effectiveness of LAIV4 against influenza of any virus type was estimated at 54.2% (95% confidence interval, 32.2%-69.0%), 20.3% (-12.7% to 43.6%) and 30.5% (10.9%-45.9%); the corresponding effectiveness of IIV3 was 77.2% (48.9%-89.8%), 24.5% (-29.8% to 56.1%) and -20.1% (-61.5% to 10.7%). Neither of the influenza vaccines clearly excelled in protecting children. The LAIV4 effectiveness against type B was greater than against type A and greater than the IIV3 effectiveness against type B. CONCLUSIONS:To understand how influenza vaccines could be improved, vaccine effectiveness must be analyzed by vaccine and virus type. Effectiveness estimates expressing also overall protection levels are needed to guide individual and programmatic decision-making processes. Supported by this analysis, the vaccination program in Finland now recommends LAIV4 and injectable, tetravalent inactivated influenza vaccines replacing IIV3.
METHODS::Intranasally administered influenza vaccines could be more effective than injected vaccines, since intranasal vaccination can induce virus-specific IgA antibodies in the upper respiratory tract, which is the initial site of infection. In the current study, immune responses elicited by an intranasal inactivated H5 influenza vaccine were evaluated in healthy H5 influenza virus-naive individuals. Three doses of intranasal inactivated whole-virion H5 influenza vaccine induced strong neutralizing nasal IgA and serum IgG antibodies. In addition, a mucoadhesive excipient, carboxy-vinyl polymer (CVP), had a notable impact on the induction of nasal IgA antibody responses but not serum IgG antibody responses. The nasal hemagglutinin (HA)-specific IgA antibody responses clearly correlated with mucosal neutralizing antibody responses, indicating that measurement of nasal HA-specific IgA titers could be used as a surrogate for the mucosal antibody response. Furthermore, increased numbers of plasma cells and vaccine antigen-specific helper T (Th) cells in the peripheral blood were observed after vaccination, suggesting that peripheral blood biomarkers may also be used to evaluate the intranasal vaccine-induced immune response. However, peripheral blood immune cell responses correlated with neutralizing antibody titers in serum samples but not in nasal wash samples. Thus, analysis of the peripheral blood immune response could be a surrogate for the systemic immune response to intranasal vaccination but not for the mucosal immune response. The current study suggests the clinical potential of intranasal inactivated vaccines against H5 influenza viruses and highlights the need to develop novel means to evaluate intranasal vaccine-induced mucosal immune responses. This article is protected by copyright. All rights reserved.
METHODS:BACKGROUND:Influenza is an important public health problem and existing vaccines are not completely protective. New vaccines that protect by alternative mechanisms are needed to improve efficacy of influenza vaccines. In 2015, we did a phase 1 trial of an oral influenza vaccine, VXA-A1.1. A favourable safety profile and robust immunogenicity results in that trial supported progression of the vaccine to the current phase 2 trial. The aim of this study was to evaluate efficacy of the vaccine in a human influenza challenge model. METHODS:We did a single-site, placebo-controlled and active-controlled, phase 2 study at WCCT Global, Costa Mesa, CA, USA. Eligible individuals had an initial A/California/H1N1 haemagglutination inhibition titre of less than 20 and were aged 18-49 years and in good health. Individuals were randomly assigned (2:2:1) to receive a single immunisation of either 1011 infectious units of VXA-A1.1 (a monovalent tablet vaccine) orally, a full human dose of quadrivalent inactivated influenza vaccine (IIV) via intramuscular injection, or matched placebo. Randomisation was done by computer-generated assignments with block size of five. An unmasked pharmacist provided the appropriate vaccines and placebos to the administrating nurse. Individuals receiving the treatments, investigators, and staff were all masked to group assignments. 90 days after immunisation, individuals without clinically significant symptoms or signs of influenza, an oral temperature of higher than 37·9°C, a positive result for respiratory viral shedding on a Biofire test, and any investigator-assessed contraindications were challenged intranasally with 0·5 mL wild-type A/CA/like(H1N1)pdm09 influenza virus. The primary outcomes were safety, which was assessed in all immunised participants through 365 days, and influenza-positive illness after viral challenge, which was assessed in individuals that received the viral challenge and the required number of assessments post viral challenge. This trial is registered with ClinicalTrials.gov, number NCT02918006. RESULTS:Between Aug 31, 2016, and Jan 23, 2017, 374 individuals were assessed for eligibility, of whom 179 were randomly assigned to receive either VXA-A1.1 (n=71 [one individual did not provide a diary card, thus the solicited events were assessed in 70 individuals]), IIV (n=72), or placebo (n=36). Between Dec 2, 2016, and April 26, 2017, 143 eligible individuals (58 in the VXA-A1.1 group, 54 in the IIV group, and 31 in the placebo group) were challenged with influenza virus. VXA-A1.1 was well tolerated with no serious or medically significant adverse events. The most prevalent solicited adverse events for each of the treatment groups after immunisation were headache in the VXA-A1.1 (in five [7%] of 70 participants) and placebo (in seven [19%] of 36 participants) groups and tenderness at injection site in the IIV group (in 19 [26%] of 72 participants) Influenza-positive illness after challenge was detected in 17 (29%) of 58 individuals in the VXA-A1.1 group, 19 (35%) of 54 in the IIV group, and 15 (48%) of 31 in the placebo group. INTERPRETATION:Orally administered VXA-A1.1 was well tolerated and generated protective immunity against virus shedding, similar to a licensed intramuscular IIV. These results represent a major step forward in developing a safe and effective oral influenza vaccine. FUNDING:Department of Health and Human Services, Office of the Assistant Secretary for Preparedness and Response, and Biomedical Advanced Research and Development Authority.