Passive immunization for influenza through antibody therapies,a review of the pipeline,challenges and potential applications

The Global Action Plan for influenza vaccines (GAP) aims to increase the production capacity of vaccines so that in the event of a pandemic there is an adequate supply to meet global needs. However, it has been estimated that even in the best case scenario there would be a considerable delay of at least five to six months for the first supplies of vaccine to become available after the isolation of the strain and availability of the candidate vaccine virus to vaccine manufacturers. By this time, the virus is likely to have already infected millions of people worldwide, causing significant mortality, morbidity and economic loss.Passive immunization through broadly neutralizing antibodies which bind to multiple, structurally diverse strains of influenza could be a promising solution to address the immediate health threat of an influenza pandemic while vaccines are being developed. These products may also have a role in seasonal influenza as an alternative to other options such as antivirals for the treatment of severe acute respiratory illness due to influenza.This article provides an overview of the current clinical pipeline of anti-influenza antibodies and discusses potential uses and the challenges to product development.     

Report on the first WHO integrated meeting on development and clinical trials of influenza vaccines that induce broadly protective and long-lasting immune responses : Hong Kong SAR,China, 24–26 January 2013

On January 24–26, 2013, the World Health Organization convened the first integrated meeting on “The development and clinical trials of vaccines that induce broadly protective and long-lasting immune responses” to review the current status of development and clinical evaluation of novel influenza vaccines as well as strategies to produce and deliver vaccines in novel ways. Special attention was given to the development of possible universal influenza vaccines. Other topics that were addressed included an update on clinical trials of pandemic and seasonal influenza vaccines in high-risk groups and vaccine safety, as well as regulatory issues.     

Evaluation of safety and immunogenicity of recombinant influenza hemagglutinin (H5/Indonesia/05/2005) formulated with and without a stable oil-in-water emulsion containing glucopyranosyl-lipid A (SE + GLA) adjuvant

Background

Expression of recombinant hemagglutinin (rHA) in insect cells represents a technology with proven efficacy in seasonal influenza and with the potential for a rapid response to the emergence of new, pandemic strains. We evaluated the safety and immunogenicity of rHA vaccine (H5/Indonesia/5/05) produced in SF+ insect cells using a baculovirus expression vector system (BEVS). The rHA vaccine was tested with and without the adjuvant glucopyranosyl lipid A/stable emulsion (GLA/SE).

Methods

Healthy adults 18–49 were randomized to two IM doses on Days 0 and 21 of placebo; unadjuvanted rHA 135 μg or 45 μg, or rHA 45 μg, 15 μg, 7.5 μg or 3.8 μg with GLA/SE. A pioneer group was monitored through Day 42 before randomizing remaining subjects. H5-specific antibody was determined by hemagglutination inhibition (HAI) and microneutralization (MN) on Days 0, 21 and 42.

Results

392 subjects were randomized, of whom 380 (97%) received two doses and 386 (98%) completed 12 months of follow-up. Injection site pain and tenderness were seen in 50–70% of rHA + GLA/SE recipients and 4–9% of rHA alone and placebo recipients, but most complaints were mild to moderate in intensity. After two doses, the proportions of subjects with HAI titers ≥1:40 were 32% and 15% in the unadjuvanted 135 μg and 45 μg groups, and 82%, 75%, 66%, and 72% in those receiving 45 μg, 15 μg, 7.5 μg, or 3.8 μg with GLA/SE. The geometric mean titers (GMTs) of HAI antibody on Day 42 were 128, 95, 69, and 72 in the 45 μg, 15 μg, 7.5 μg, or 3.8 μg with GLA/SE groups, respectively.

Conclusions

rHA GLA/SE was well tolerated and immunogenic in healthy adults, and GLA/SE substantially improved the serum antibody response. rHA expressed using BEVS recombinant DNA platform technology represents a promising strategy for pandemic control.     

Live attenuated seasonal and pandemic influenza vaccine in school-age children: A randomized controlled trial

Background

The novel influenza A(H1N1pdm09) virus emerged in North America in early 2009 and rapidly spread worldwide. In this study we report the efficacy of the live attenuated monovalent H1N1pdm09 vaccine and 2009–10 seasonal influenza vaccine in a randomized double-blind placebo-controlled trial.

Methods

We enrolled 703 children aged 7–11. Each child was randomly allocated in the ratio 3:2 to receive one dose of live attenuated monovalent H1N1pdm09 vaccine or saline placebo between November 2009 and January 2010, followed after 3–10 weeks by independent random allocation to one dose of live attenuated trivalent 2009–10 seasonal influenza vaccine or saline placebo in the same ratio. Children were followed up through September 2010 with biweekly telephone calls and symptom diaries. Seasonal and pandemic influenza infections were confirmed by virologic testing of nose and throat swabs collected during acute respiratory illnesses.

Results

Overall, 30 children had confirmed influenza including 3 (0.43%) H1N1pdm09, 10 (1.4%) seasonal A(H3N2), and 17 (2.4%) influenza B. There were no significant differences in incidence rates of H1N1pdm09 or A(H3N2) between the four study arms, but receipt of the seasonal influenza vaccine was associated with a significant reduction in risk of influenza B (p < 0.01). Vaccine efficacy against confirmed H1N1pdm09 infection associated with receipt of the monovalent H1N1pdm09 vaccine was 65% (95% confidence interval, CI: −281%, 97%). Vaccine efficacies against confirmed seasonal influenza A(H3N2) and B infection associated with receipt of the seasonal influenza vaccine were 31% (95% CI: −138%, 80%) and 96% (95% CI: 67%, 99%) respectively.

Conclusions

Vaccine efficacy was consistent with other studies of the monovalent H1N1pdm09 vaccine and seasonal influenza vaccines. Our study was underpowered to provide precise estimates of vaccine efficacy due to low incidence of influenza A viruses during the study period.     

Nurses' vaccination against pandemic H1N1 influenza and their knowledge and other factors

This study aimed to estimate the vaccination coverage against the pandemic H1N1 influenza in a group of nurses and determine the factors associated with their vaccination behaviours. An anonymous, self-administered questionnaire was distributed to a convenience sample of nurses who were enrolled on continuing professional education courses in a university in London. The survey response rate was 77.7% (n=522). A total of 172 (35.2%) nurses reported receiving the pandemic H1N1 vaccine in the 2009-2010 influenza season and only 22.3% of them had the intent to accept the vaccine in the next season. Compared to nurses with low knowledge scores, those with high knowledge scores were more likely to receive the pandemic H1N1 vaccine (p=0.017), recommend the vaccine to their patients (p=0.003), and have the willingness to recommend vaccination to patients in the future (p=0.009). There was a higher vaccination rate among nurses with higher risk perception scores than with lower scores (p=0.001). A small, positive correlation between H1N1 knowledge and risk perception scores was identified (p<0.001) indicating that a high knowledge level was associated with high levels of risk perception. More male nurses received the H1N1 vaccine than females (p<0.001) and there were a significant differences in the uptake among nurses from different clinical specialty groups (p<0.001). About half of the vaccinated nurses reported the intent to be vaccinated again but only 8.1% of the unvaccinated nurses had the intent to receive the vaccine in the next season (p<0.001). The pandemic H1N1 2009 influenza vaccination coverage among this nurse sample was sub-optional. Lack of knowledge and risk perception were predictors associated with the nurses' vaccination behaviours. The identified knowledge items should be addressed in future vaccination campaigns. The hindrances associated with continuing vaccination decision-making and factors contributing to the different vaccination coverage among clinical specialty groups require further exploration.     

Pre-vaccination immunity and immune responses to a cell culture-derived whole-virus H1N1 vaccine are similar to a seasonal influenza vaccine

Background

Immune responses to novel pandemic influenza vaccines may be influenced by previous exposure to antigenically similar seasonal strains.

Methods

An open-label, randomized, phase I/II study was conducted to assess the immunogenicity and safety of a non-adjuvanted, inactivated whole-virus H1N1 A/California/07/2009 vaccine. 408 subjects were stratified by age (18–59 and >60 years) and randomized 1:1 to receive two vaccinations with either 3.75 or 7.5 μg hemagglutinin antigen 21 days apart. Safety, immunogenicity and the influence of seasonal influenza vaccination and antibody cross-reactivity with a seasonal H1N1 strain was assessed.

Results

A single vaccination with either dose induced substantial increases in H1N1 A/California/07/2009 hemagglutination inhibition (HI) and neutralizing (MN) antibody titers in both adult and elderly subjects. A single 7.5 μg dose induced seroprotection rates of 86.9% in adults and 75.2% in elderly subjects. Two 7.5 μg vaccinations induced seroprotection rates in adult and elderly subjects of 90.9% and 89.1%, respectively. The robust immune response to vaccination was confirmed by analyses of neutralizing antibody titers. Both HI and MN antibodies persisted for ≥6 months post-vaccination. Between 34% and 49% of subjects had seroprotective levels of H1N1 A/California/07/2009 antibodies at baseline. Higher baseline HI titers were associated with receipt of the 2008–09 or 2009–10 seasonal influenza vaccine. High baseline A/California/07/2009 neutralizing antibody titers were also associated with high baseline titers against A/New Caledonia/20/99, a seasonal H1N1 strain which circulated and was included in the seasonal vaccine from 2000–01 to 2006–07. Pre-adsorption with A/H1N1/New Caledonia/20/99 antigen reduced A/H1N1/California/07/2009 baseline titers in 55% of tested sera. The vaccine was well tolerated with low rates of fever.

Conclusions

A whole-virus H1N1 A/California/07/2009 vaccine was safe and well tolerated and a single dose induced substantial immune responses similar to seasonal influenza vaccines, probably due to immunological priming by previous seasonal influenza vaccines or infections.     

Safety and immunogenicity of 2010-2011 H1N12009-containing trivalent inactivated influenza vaccine in children 12-59 months of age previously given AS03-adjuvanted H1N12009 pandemic vaccine: a PHAC/CIHR Influenza Research Network (PCIRN) study

Background

Concern arose in 2010 that reactogenicity, particularly febrile seizures, to influenza A/H1N1-containing 2010–2011 trivalent seasonal inactivated influenza vaccine (TIV) could occur in young children who had been previously immunized and/or infected with the pandemic strain. We conducted a pre-season study of 2010–2011 TIV safety and immunogenicity in children 12–59 months of age to inform public health decision making.

Methods

Children immunized with 1 or 2 doses of the pandemic vaccine, with or without the 2009–10 TIV, received 1 or 2 doses of 2010–11 TIV in an observational, multicentre Canadian study. Standard safety monitoring was enhanced by a telephone call at ∼24 h post-TIV when adverse events were expected to peak. Summary safety reports were rapidly reported to public health before the launch of public programs. TIV immunogenicity was assessed day 0, and 21 days after final vaccination. Clinical Trials Registration NCT01180621.

Results

Among 207 children, a general adverse event was reported by 60.9% of children post-dose one and by 58.3% post-dose two. Only severe fever (>38.5 °C) was more common in two-dose compared to one dose recipients (16.7%, n = 4 v. 1.0%, n = 2). At baseline 99.0% of participants had A/H1N1 hemagglutinin inhibition (HAI) titers ≥10, and 85.5% had a protective titer of ≥40 (95% CI 80.0, 90.0). Baseline geometric mean titers (GMT) were higher in recipients of a 2-dose schedule of pandemic vaccine compared to one-dose recipients: 153.1 (95% CI 126.2, 185.7) v. 78.8 ((58.1, 106.8, p < 0.001). At 21 days, all regulatory criteria for influenza vaccine immunogenicity were exceeded for A/H1N1 and H3N2, but responses to the B antigen were poor. No correlations between reactogenicity and either baseline high influenza titers or serologic response to revaccination were evident.

Conclusions

Infants and toddlers who received AS03-adjuvanted A/H1N1 2009 vaccine up to 11 months earlier retained high titers in the subsequent season but re-exposure to A/H1N1 2009 antigen in TIV resulted in no unusual adverse effects and 100% were sero-protected for A/H1N1 after receipt of the 2010–11 TIV.     

甲型H1N1流感大流行前后沈阳地区流感病原学流行特征

目的分析甲型H1N1流行性感冒(流感)大流行前后沈阳流感病原学流行特征。方法采集2005年10月—2011年3月连续5.5 a哨点医院的流感样病例咽拭子,进行流感病毒的分离和分型鉴定,并按甲型H1N1流感流行前后划分为3个时期。结果 3个时期共采集流感样病例咽拭子样本6 808份,分离到流感病毒861株,总分离率为12.6%;流行前、流行中和流行后3个时期流感病毒检出率分别为13.8%、18.2%和5.2%。男性和女性流感病毒感染率差异无统计学意义,不同时期流感样病例的年龄构成差异有统计学意义。新的甲型H1N1流感侵袭的人群主要是低年龄组人群,新的甲型H1N1流行期间和流行后,流感季节高峰发生前移。不同年度流感流行毒株型别不同,前1年监测周期的优势株在下1个周期中可被其他型别抑制甚至取代。结论甲型H1N1流感流行后沈阳的流感流行特征已发生了部分改变,这种改变是否持续存在还有待持续监测来得以验证,在2011—2012年监测周期中应密切关注A3(H3N2)亚型和新的甲型H1N1亚型流感毒株的活动情况。     

中国五省(区)市疾病预防控制机构流感大流行应对能力现状研究

目的了解浙江、新疆、山东、贵州、武汉五省(区)市疾病预防控制机构的流感大流行应对能力现状,研究针对性干预措施。方法对五省(区)市的59家疾病预防控制中心进行问卷调查,数据进行描述流行病学分析。结果调查的各级疾控中心均成立了应急处置组织体系,制定了流感大流行应急预案并开展演练和培训;75.00%的省级、55.56%的市级和51.35%的县级疾控中心认为储备的消毒药品不能满足重大突发公共卫生事件的处置需求;省、市级疾控中心均具备流感病毒检测能力,但县级疾控中心仅浙江省有69.57%可以开展检测。结论五省(区)市疾控机构具备了应对流感大流行的基本专业技术能力,但仍存在人才队伍数量不足、应急物资储备机制不完善、监测系统建设东西部发展不均衡、基层流感病毒检测能力薄弱等问题,亟需加强和改进。     

北京市怀柔区人群甲型H1N1流感抗体的血清学研究

目的:研究北京市怀柔区普通人群中甲型H1N1流感病毒抗体的分布情况并阐明其特点。方法:自2010年1月开始,选取怀柔区共2323名调查对象进行回顾性问卷调查,并采集血清标本进行甲型H1N1流感病毒血凝抑制抗体(HI)水平的检测。结果:31.38%的调查对象体内HI抗体为阳性。接种疫苗者的血清学反应阳性率为40.45%,未接种疫苗但血清学反应阳性并出现呼吸道感染症状的可达26.57%。不同年龄组的HI抗体阳性率也不同(P<0.01)。多因素Logistic回归表明年龄、职业、是否集体生活、H1N1疫苗接种史和抗体滴度有关,性别对HI抗体阳性率则无明显的差异。结论:研究表明怀柔区普通居民体内都有一定的HI抗体滴度,从而可能对H1N1流感病毒起到一定的免疫功能;这同北京市早期的相关报道是相一致的。