Enhanced passive safety surveillance of a trivalent and a quadrivalent influenza vaccine in Denmark and Finland during the 2018/2019 season

The European Medicines Agency requires Enhanced Passive Safety Surveillance (EPSS) for all seasonal influenza vaccines. Here, we report the EPSS results for the trivalent inactivated influenza vaccine (IIV3; Vaxigrip®) and the quadrivalent inactivated influenza vaccine (IIV4; VaxigripTetraTM) during the 2018/19 influenza season in Denmark and Finland. The primary objective was to estimate the rates of suspected adverse reactions (ARs) occurring within 7 days following routine vaccination. Between October and November 2018, 1000 safety report cards (SRCs) for IIV3 were distributed in Denmark, and 996 SRCs for IIV4 were distributed in Finland. Participants were instructed to report any ARs by telephone or e-mail using the information provided on the SRC. All participants vaccinated with IIV3 were aged ≥18 years. Most participants vaccinated with IIV4 (95.5%) were aged 18 − 65 years, 2.2% were aged 6 months to 17 years, and 2.3% were aged >65 years. Fifty-five ARs were reported by 12 participants (1.2%) vaccinated with IIV3 and 162 ARs were reported by 53 participants (5.3%) vaccinated with IIV4. The most frequent ARs were vaccination site pain and fever for IIV3, and vaccination site pain, vaccination site inflammation, myalgia, and headache for IIV4. The 2018/19 AR rates for IIV3 were comparable to 2017/18 rates. The 2018/19 AR rates for IIV4 were higher than those in 2017/18 but were still lower than the expected AR rates listed in the IIV4 Summary of Product Characteristics. In conclusion, the 2018/19 EPSS showed no clinically significant change from the expected safety profiles of IIV3 and IIV4 vaccines

Enhanced passive safety surveillance of three marketed influenza vaccines in the UK and the Republic of Ireland during the 2017/18 season

Safety surveillance is required for each season’s influenza vaccines to rapidly detect and evaluate potential new safety concerns before the peak period of immunization. Here we report the results of an enhanced passive safety surveillance for a trivalent split-virion inactivated influenza vaccine (IIV3; Vaxigrip®), an intradermal version of this vaccine (IIV3-ID; Intanza® 15 µg), and a recently licensed quadrivalent version (IIV4; VaxigripTetraTM) during the 2017/18 influenza season in the UK and Republic of Ireland. The primary objective was to determine the rates of adverse reactions (ARs) occurring within 7 days following routine vaccination. Between September and November 2017, 979 safety report cards were distributed to vaccinees receiving IIV3-ID, 1005 to those receiving IIV3, and 957 to those receiving IIV4. At least one AR was reported by 28 participants (2.9%) vaccinated with IIV3-ID, 14 participants (1.4%) vaccinated with IIV3, and 20 participants (2.1%) vaccinated with IIV4. The most frequent ARs were injection-site reactions and headache. One participant vaccinated with IIV3-ID reported two suspected serious ARs (dyskinesia and a shock symptom), although these could not be confirmed as vaccine-related. Rates of ARs for IIV3 and IIV3-ID for 2017/18 did not differ from the 2016/17 rates. For IIV4, in its first season since licensure, AR frequencies were similar to those in the Summary of Product Characteristics. In conclusion, no change was found compared to the known or expected AR rates for IIV3, IIV3-ID, or IIV4 during the 2017/18 season

Epidemiology and burden of influenza in healthy children aged 6 to 35 months: analysis of data from the placebo arm of a phase III efficacy trial

Abstract Background Despite World Health Organization recommendations, in many countries young children are not targeted for influenza vaccination. To help inform influenza vaccination policy, we examined the occurrence and burden of influenza in healthy children aged 6 to 35 months using data from a recent phase III placebo-controlled influenza vaccine trial conducted in countries in the Northern and Southern Hemispheres. Methods This was an analysis of data from participants included in the placebo arm of a phase III clinical trial in healthy children aged 6 to 35 months (EudraCT no. 2013–001231-51). Included children had never been vaccinated for influenza and were observed for one influenza season. Outcome measures included the occurrence of influenza-like illness (ILI), laboratory-confirmed influenza, virus types/subtypes, severe symptoms and complications of confirmed influenza, and healthcare use associated with confirmed influenza. Results Data from 2210 participants were analysed. ILI was reported for 811 participants (36.7%). Of these, 255 participants (31.4%) had 263 virologically confirmed episodes of influenza. The overall influenza attack rate was 11.5%. The most common influenza virus detected was A(H3N2) (40.7%), followed by B/Yamagata (23.6%), A(H1N1) (18.6%), and B/Victoria (8.0%). Grade 3 fever was reported in 24.3% of confirmed episodes, acute lower respiratory infection in 8.7%, acute otitis media in 6.1%, and pneumonia in 1.9%. In most influenza episodes (93.2%), antipyretics, analgesics, or non-steroidal anti-inflammatory drugs were taken. Antibiotics were prescribed for 41.4% of influenza episodes. More than half of the influenza episodes (57.0%) resulted in outpatient visits. Influenza resulted in overnight hospitalisation in 1.1% of episodes. Conclusions Influenza is associated with a significant burden of disease in healthy children. This analysis also revealed that antibiotics continue to be frequently used for young children with influenza. Trial registration EudraCT no. 2013–001231-51

Safety and immunogenicity of three dose levels of an investigational, highly purified Vero cell rabies vaccine: A randomized, controlled, observer-blinded, Phase II study with a simulated post-exposure regimen in healthy adults

ABSTRACTA serum-free, highly purified rabies vaccine produced in Vero cells is under development. The initial formulation, PVRV-NG, was evaluated in five Phase II studies and subsequently reformulated (PVRV-NG2). This multicenter, observer-blinded Phase II study investigated the safety and immune response of three different doses (antigen content) of PVRV-NG2 versus a licensed human diploid cell rabies vaccine (HDCV; Imovax rabies®). Healthy adults (N = 320) were randomized to receive PVRV-NG2 (low, medium, or high dose), PVRV-NG, or HDCV (2:2:2:1:1 ratio), according to a five-dose Essen simulated post-exposure regimen (Days [D] 0, 3, 7, 14, and 28). All participants received human rabies immunoglobulin intramuscularly on D0. Immunogenicity was assessed at D0, 14, 28, 42, and 6 months after the final injection using the rapid fluorescent focus inhibition test. Seroconversion rates were calculated as the percentage of participants achieving rabies virus neutralizing antibody titers ≥0.5 IU/mL. All analyses were descriptive. At each timepoint, geometric mean titers (GMTs) increased with antigen content (measured using an enzyme-linked immunosorbent assay). High-dose PVRV-NG2 GMTs were the highest at all timepoints, medium-dose PVRV-NG2 GMTs were similar to those with HDCV, and low-dose PVRV-NG2 GMTs were similar to PVRV-NG. The safety profile of PVRV-NG2 was comparable to PVRV-NG; however, fewer injection site reactions were reported with PVRV-NG2 or PVRV-NG (range 36.7–47.5%) than with HDCV (61.5%). This study demonstrated a dose–effect of antigen content at all timepoints. As post-exposure prophylaxis, the safety and immunogenicity profiles of the high-dose PVRV-NG2 group compared favorably with HDCV. Clinicaltrials.gov number: NCT03145766

Meningococcal serogroups and surveillance: a systematic review and survey

Background: Meningococcal disease continues to be a global public health concern due to its epidemic potential, severity, and sequelae. The global epidemiological data on circulating meningococcal serogroups have never been reviewed concurrently with the laboratory capacity for meningococcal surveillance at the national level. We, therefore, aimed to conduct a country-level review of meningococcal surveillance, serogroup distribution, and vaccine use. Methods: We conducted a systematic literature review across six databases to identify studies (published January 1, 2010 to October 16, 2017) and grey literature reporting meningococcal serogroup data for the years 2010-2016. We performed independent random effects meta-analyses for serogroups A, B, C, W, X, Y, and other. We developed and circulated a questionnaire-based survey to surveillance focal points in countries (N = 95) with known regional bacterial meningitis surveillance programs to assess their surveillance capacity and summarized using descriptive methods. Results: We included 173 studies from 59 countries in the final analysis. The distribution of meningococcal serogroups differed markedly between countries and regions. Meningococcal serogroups C and W accounted for substantial proportions of meningococcal disease in most of Africa and Latin America. Serogroup B was the predominant cause of meningococcal disease in many locations in Europe, the Americas, and the Western Pacific. Serogroup Y also caused many cases of meningococcal disease in these regions, particularly in Nordic countries. Survey responses were received from 51 countries. All countries reported the ability to confirm the pathogen in-country, while approximately 30% either relied on reference laboratories for serogrouping (N = 10) or did not serogroup specimens (N = 5). Approximately half of countries did not utilize active laboratory-based surveillance system (N = 22). Nationwide use of a meningococcal vaccine varied, but most countries (N = 36) utilized a meningococcal vaccine at least for certain high-risk population groups, in private care, or during outbreaks. Conclusions: Due to the large geographical variations in circulating meningococcal serogroups, each country should continue to be monitored for changes in major disease-causing serogroups in order to inform vaccine and control policies. Similarly, laboratory capacity should be appropriately scaled up to more accurately understand local epidemiology and disease burden, as well as the impact of vaccination programs.Funding: This study was funded by Sanofi Pasteur. MHK and AM are employees of Sanofi Pasteur and had a role in study design, data interpretation, and preparation of the manuscript. YL is supported by a scholarship from the China Scholarship Council. l had no roThe China Scholarship Councile in study design, data interpretation, or preparation of the manuscript. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication.S

Dengue serotype-specific seroprevalence among 5- to 10-year-old children in India: a community-based cross-sectional study

Background: Dengue surveillance data in India are limited and probably substantially underestimate the burden of disease. A community-based study was undertaken to assess the prevalence of dengue-specific immunoglobulin G (IgG) antibodies in children across India and to examine historical dengue exposure rates. Potential associations between socio-economic factors and dengue seroprevalence were also assessed (registered at ctri.nic.in: CTRI/2011/12/002243). Methods: A convenience sample of 2609 healthy children aged 5–10 years was enrolled; these children were registered at or were living in the vicinity of eight centres located at six geographically distinct sites across India. Blood samples were drawn to test for the presence of dengue IgG antibodies using ELISA. Serotype-specific neutralizing antibody titres were measured in dengue IgG-positive children using dengue plaque reduction neutralization tests. Socio-demographic and household information was collected using a questionnaire. Results: Overall, 2558/2609 children had viable samples with laboratory results for dengue IgG. Dengue IgG seroprevalence across all sites was 59.6% (95% confidence interval 57.7–61.5%): the lowest (23.2%) was in Kalyani, West Bengal, and the highest (80.1%) was in Mumbai. Seroprevalence increased with age. Multivariate analysis suggested associations with household water storage/supply and type of housing. Half of the subjects with positive IgG results presented a multitypic profile, indicating previous exposure to more than one serotype. Conclusions: The overall dengue seroprevalence suggests that dengue endemicity in India is comparable to that in highly endemic countries of Southeast Asia. Additional prospective studies are required to fully quantify the disease burden, in order to support evidence-based policies for dengue prevention and control in India

Age distribution of dengue cases in southern Vietnam from 2000 to 2015.

BackgroundDengue is the most common vector-borne viral infection. In recent times, an increase in the age of cases with clinical dengue has been reported in the national surveillance system and published literature of Vietnam. This change not only alter the risk of transmission and disease burden in different populations but also will impact for prevention and control strategies. A retrospective study was conducted from 2000 to 2015 in 19 provinces of southern Vietnam to describe the changes in age distribution of dengue cases and circulating serotypes.Methodology/principal findingsThe study is a time trend analysis of the data aggregated from the database of dengue surveillance system. The database consisted of clinically diagnosed and laboratory-confirmed cases of dengue in southern Vietnam from 2000 to 2015. In the study period, the mean age of dengue cases increased from 12.2 ± 8.8 years old (y/o) to 16.8 ± 13.3 y/o between 2000 and 2015. Majority of severe cases were observed in the age group of 5-9 y/o and 10-14 y/o. Overall, the mortality and case fatality rates (CFR) were lowest during 2010 to 2015, and all four serotypes of dengue were observed.Conclusions/significanceWith the exception of severe form, the age distribution of clinical cases of dengue appears to be shifting towards older age groups. An increase in the mean age of clinical cases of dengue has been observed in southern Vietnam over the past decade, and the highest incidence was observed in age group of 5-14 y/o. All serotypes of dengue were in circulation

T cells, more than antibodies, may prevent symptoms developing from respiratory syncytial virus infections in older adults

Abstract: IntroductionThe immune mechanisms supporting partial protection from reinfection and disease by the respiratory syncytial virus (RSV) have not been fully characterized. In older adults, symptoms are typically mild but can be serious in patients with comorbidities when the infection extends to the lower respiratory tract.MethodsThis study formed part of the RESCEU older-adults prospective-cohort study in Northern Europe (2017-2019; NCT03621930) in which a thousand participants were followed over an RSV season. Peripheral-blood samples (taken pre-season, post-season, during illness and convalescence) were analyzed from participants who (i) had a symptomatic acute respiratory tract infection by RSV (RSV-ARTI; N=35) or (ii) asymptomatic RSV infection (RSV-Asymptomatic; N=16). These analyses included evaluations of antibody (Fc-mediated-) functional features and cell-mediated immunity, in which univariate and machine-learning (ML) models were used to explore differences between groups.ResultsPre-RSV-season peripheral-blood biomarkers were predictive of symptomatic RSV infection. T-cell data were more predictive than functional antibody data (area under receiver operating characteristic curve [AUROC] for the models were 99% and 76%, respectively). The pre-RSV season T-cell phenotypes which were selected by the ML modelling and which were more frequent in RSV-Asymptomatic group than in the RSV-ARTI group, coincided with prominent phenotypes identified during convalescence from RSV-ARTI (e.g., IFN-gamma+, TNF-alpha+ and CD40L+ for CD4+, and IFN-gamma+ and 4-1BB+ for CD8+).ConclusionThe evaluation and statistical modelling of numerous immunological parameters over the RSV season suggests a primary role of cellular immunity in preventing symptomatic RSV infections in older adults

Association of rotavirus strains and severity of gastroenteritis in Indian children

Rotavirus is the leading cause of severe and dehydrating diarrhea in children aged under 5 years. We undertook this hospital-based surveillance study to examine the possible relationship between the severity of diarrhea and the various G-group rotaviruses circulating in India. Stool samples (n = 2,051) were systematically collected from 4,711 children aged <5 years admitted with severe acute gastroenteritis to 12 medical school centers from April 2011 to July 2012. Rotavirus testing was undertaken using a commercially available enzyme immunoassay kit for the rotavirus VP6 antigen (Premier Rotaclone Qualitative ELISA). Rotavirus positive samples were genotyped for VP7 and VP4 antigens by reverse-transcription polymerase chain reaction at a central laboratory. Of the stool samples tested for rotavirus antigen, 541 (26.4%) were positive for VP6 antigen. Single serotype infections from 377 stool samples were compared in terms of gastroenteritis severity. Among those with G1 rotavirus infection, very severe diarrhea (Vesikari score ≥ 16) was reported in 59 (33.9%) children, severe diarrhea (Vesikari score 11–15) in 104 (59.8%), moderate (Vesikari score 6–10) and mild diarrhea (Vesikari score 0–5) in 11 (6.3%). Among those with G2 infection, very severe diarrhea was reported in 26 (27.4%) children, severe diarrhea in 46 (48.4%), and moderate and mild diarrhea in 23 (24.2 %). Among those with G9 infection, very severe diarrhea was reported in 47 (54.5%) children, severe diarrhea in 29 (33.6%), and moderate and mild diarrhea in 10 (11.9%). Among those with G12 infection, very severe diarrhea was reported in 9 (40.9%) children and severe diarrhea in 13 (59.1%). The results of this study indicate some association between rotavirus serotypes and severity of gastroenteritis

Symptomatic Dengue Disease in Five Southeast Asian Countries: Epidemiological Evidence from a Dengue Vaccine Trial

<div><p>Dengue incidence has increased globally, but empirical burden estimates are scarce. Prospective methods are best-able to capture all severities of disease. CYD14 was an observer-blinded dengue vaccine study conducted in children 2–14 years of age in Indonesia, Malaysia, Thailand, the Philippines, and Vietnam. The control group received no vaccine and resembled a prospective, observational study. We calculated the rates of dengue according to different laboratory or clinical criteria to make inferences about dengue burden, and compared with rates reported in the passive surveillance systems to calculate expansion factors which describe under-reporting. Over 6,933 person-years of observation in the control group there were 319 virologically confirmed dengue cases, a crude attack rate of 4.6%/year. Of these, 92 cases (28.8%) were clinically diagnosed as dengue fever or dengue hemorrhagic fever by investigators and 227 were not, indicating that most symptomatic disease fails to satisfy existing case definitions. When examining different case definitions, there was an inverse relationship between clinical severity and observed incidence rates. CYD14’s active surveillance system captured a greater proportion of symptomatic dengue than national passive surveillance systems, giving rise to expansion factors ranging from 0.5 to 31.7. This analysis showed substantial, unpredictable and variable under-reporting of symptomatic dengue, even within a controlled clinical trial environment, and emphasizes that burden estimates are highly sensitive to case definitions. These data will assist in generating disease burden estimates and have important policy implications when considering the introduction and health economics of dengue prevention and control interventions.</p></div