The global epidemiology of chikungunya from 1999 to 2020: A systematic literature review to inform the development and introduction of vaccines.

Chikungunya fever is an acute febrile illness that is often associated with severe polyarthralgia in humans. The disease is caused by chikungunya virus (CHIKV), a mosquito-borne alphavirus. Since its reemergence in 2004, the virus has spread throughout the tropical world and several subtropical areas affecting millions of people to become a global public health issue. Given the significant disease burden, there is a need for medical countermeasures and several vaccine candidates are in clinical development. To characterize the global epidemiology of chikungunya and inform vaccine development, we undertook a systematic literature review in MEDLINE and additional public domain sources published up to June 13, 2020 and assessed epidemiological trends from 1999 to 2020. Observational studies addressing CHIKV epidemiology were included and studies not reporting primary data were excluded. Only descriptive analyses were conducted. Of 3,883 relevant sources identified, 371 were eligible for inclusion. 46% of the included studies were published after 2016. Ninety-seven outbreak reports from 45 countries and 50 seroprevalence studies from 31 countries were retrieved, including from Africa, Asia, Oceania, the Americas, and Europe. Several countries reported multiple outbreaks, but these were sporadic and unpredictable. Substantial gaps in epidemiological knowledge were identified, specifically granular data on disease incidence and age-specific infection rates. The retrieved studies revealed a diversity of methodologies and study designs, reflecting a lack of standardized procedures used to characterize this disease. Nevertheless, available epidemiological data emphasized the challenges to conduct vaccine efficacy trials due to disease unpredictability. A better understanding of chikungunya disease dynamics with appropriate granularity and better insights into the duration of long-term population immunity is critical to assist in the planning and success of vaccine development efforts pre and post licensure.

Paving the way for human vaccination against Rift Valley fever virus: A systematic literature review of RVFV epidemiology from 1999 to 2021.

BACKGROUND: Rift Valley fever virus (RVFV) is a lethal threat to humans and livestock in many parts of Africa, the Arabian Peninsula, and the Indian Ocean. This systematic review's objective was to consolidate understanding of RVFV epidemiology during 1999-2021 and highlight knowledge gaps relevant to plans for human vaccine trials. METHODOLOGY/PRINCIPAL FINDINGS: The review is registered with PROSPERO (CRD42020221622). Reports of RVFV infection or exposure among humans, animals, and/or vectors in Africa, the Arabian Peninsula, and the Indian Ocean during the period January 1999 to June 2021 were eligible for inclusion. Online databases were searched for publications, and supplemental materials were recovered from official reports and research colleagues. Exposures were classified into five groups: 1) acute human RVF cases, 2) acute animal cases, 3) human RVFV sero-surveys, 4) animal sero-surveys, and 5) arthropod infections. Human risk factors, circulating RVFV lineages, and surveillance methods were also tabulated. In meta-analysis of risks, summary odds ratios were computed using random-effects modeling. 1104 unique human or animal RVFV transmission events were reported in 39 countries during 1999-2021. Outbreaks among humans or animals occurred at rates of 5.8/year and 12.4/year, respectively, with Mauritania, Madagascar, Kenya, South Africa, and Sudan having the most human outbreak years. Men had greater odds of RVFV infection than women, and animal contact, butchering, milking, and handling aborted material were significantly associated with greater odds of exposure. Animal infection risk was linked to location, proximity to water, and exposure to other herds or wildlife. RVFV was detected in a variety of mosquito vectors during interepidemic periods, confirming ongoing transmission. CONCLUSIONS/SIGNIFICANCE: With broad variability in surveillance, case finding, survey design, and RVFV case confirmation, combined with uncertainty about populations-at-risk, there were inconsistent results from location to location. However, it was evident that RVFV transmission is expanding its range and frequency. Gaps assessment indicated the need to harmonize human and animal surveillance and improve diagnostics and genotyping. Given the frequency of RVFV outbreaks, human vaccination has strong potential to mitigate the impact of this now widely endemic disease.

Rural prioritization may increase the impact of COVID-19 vaccines in a representative COVAX AMC country setting due to ongoing internal migration: A modeling study.

How COVID-19 vaccine is distributed within low- and middle-income countries has received little attention outside of equity or logistical concerns but may ultimately affect campaign impact in terms of infections, severe cases, or deaths averted. In this study we examined whether subnational (urban-rural) prioritization may affect the cumulative two-year impact on disease transmission and burden of a vaccination campaign using an agent-based model of COVID-19 in a representative COVID-19 Vaccines Global Access (COVAX) Advanced Market Commitment (AMC) setting. We simulated a range of vaccination strategies that differed by urban-rural prioritization, age group prioritization, timing of introduction, and final coverage level. Urban prioritization averted more infections in only a narrow set of scenarios, when internal migration rates were low and vaccination was started by day 30 of an outbreak. Rural prioritization was the optimal strategy for all other scenarios, e.g., with higher internal migration rates or later start dates, due to the presence of a large immunological naive rural population. Among other factors, timing of the vaccination campaign was important to determining maximum impact, and delays as short as 30 days prevented larger campaigns from having the same impact as smaller campaigns that began earlier. The optimal age group for prioritization depended on choice of metric, as prioritizing older adults consistently averted more deaths across all of the scenarios. While guidelines exist for these latter factors, urban-rural allocation is an orthogonal factor that we predict to affect impact and warrants consideration as countries plan the scale-up of their vaccination campaigns.

Scientific impact increases when researchers publish in open access and international collaboration: A bibliometric analysis on poverty-related disease papers.

BACKGROUND: The European & Developing Countries Clinical Trials Partnership (EDCTP), like many other research funders, requires its grantees to make papers available via open access (OA). This article investigates the effect of publishing in OA journals and international collaboration within and between European and sub-Saharan African countries on citation impact and likelihood of falling into the top 1% and top 10% most cited papers in poverty-related disease (PRD) research. METHODS: Disease-specific research publications were identified in the Web of Science™ and MEDLINE using Medical Subject Heading (MeSH) terms. Data on the open accessibility of scientific literature were derived from 1science oaFindr. Publication data, including relative citation counts, were extracted for 2003-2015. Regression models were applied to quantify the relationship between relative citations and presence in the 1% and top 10% most cited papers versus OA and international collaboration. RESULTS: The results show that since 2003 papers on PRDs have become increasingly available in OA. Among all PRD areas, malaria research is most frequently published in OA and in international collaboration. The adjusted regression analyses show that holding other factors constant, publishing research in OA and in international collaboration has a significant and meaningful citation advantage over non-OA or non-international collaborative research. Publishing papers as part of a European-wide or European- sub-Saharan African collaboration increases research impact. In contrast, such collaboration advantage is not observed for research output involving sub-Saharan Africa only which seems to decrease research impact. CONCLUSIONS: Our results indicate that there is a real, measurable citation advantage for publishing PRD research in OA and international collaboration. However, the international collaboration advantage seems to be region-specific with increased research impact for European-wide and European-sub-Saharan African collaborations but a decrease in research impact of collaborations confined to sub-Saharan African research institutions. Further research is required to further verify this finding and to understand the underlying factors related to this observed decrease in research impact. To target future research capacity building activities in sub-Saharan Africa it is important to assess whether the observed decreased impact reflects the scientific competencies and geographic distribution of individual researchers or institutional-, national- or funder-specific research requirements.

Bibliometric Assessment of European and Sub-Saharan African Research Output on Poverty-Related and Neglected Infectious Diseases from 2003 to 2011.

BACKGROUND: The European & Developing Countries Clinical Trials Partnership (EDCTP) is a partnership of European and sub-Saharan African countries that aims to accelerate the development of medical interventions against poverty-related diseases (PRDs). A bibliometric analysis was conducted to 1) measure research output from European and African researchers on PRDs, 2) describe collaboration patterns, and 3) assess the citation impact of clinical research funded by EDCTP. METHODOLOGY/PRINCIPAL FINDINGS: Disease-specific research publications were identified in Thomson Reuters Web of Science using search terms in titles, abstracts and keywords. Publication data, including citation counts, were extracted for 2003-2011. Analyses including output, share of global papers, normalised citation impact (NCI), and geographical distribution are presented. Data are presented as five-year moving averages. European EDCTP member countries accounted for ~33% of global research output in PRDs and sub-Saharan African countries for ~10% (2007-2011). Both regions contributed more to the global research output in malaria (43.4% and 22.2%, respectively). The overall number of PRD papers from sub-Saharan Africa increased markedly (>47%) since 2003, particularly for HIV/AIDS (102%) and tuberculosis (TB) (81%), and principally involving Southern and East Africa. For 2007-2011, European and sub-Saharan African research collaboration on PRDs was highly cited compared with the world average (NCI in brackets): HIV/AIDS 1.62 (NCI: 1.16), TB 2.11 (NCI: 1.06), malaria 1.81 (NCI: 1.22), and neglected infectious diseases 1.34 (NCI: 0.97). The NCI of EDCTP-funded papers for 2003-2011 was exceptionally high for HIV/AIDS (3.24), TB (4.08) and HIV/TB co-infection (5.10) compared with global research benchmarks (1.14, 1.05 and 1.35, respectively). CONCLUSIONS: The volume and citation impact of papers from sub-Saharan Africa has increased since 2003, as has collaborative research between Europe and sub-Saharan Africa. >90% of publications from EDCTP-funded research were published in high-impact journals and are highly cited. These findings corroborate the benefit of collaborative research on PRDs.

Sustainability of National Immunization Programme (NIP) performance and financing following Global Alliance for Vaccines and Immunization (GAVI) support to the Democratic Republic of the Congo (DRC).

BACKGROUND: The Global Alliance for Vaccines and Immunization (GAVI) is a public-private global health partnership aiming to increase access to immunisation in poor countries. The Democratic Republic of the Congo (DRC) is the third largest recipient of GAVI funds in terms of cumulative disbursed support. We provided a comprehensive assessment of GAVI support and analysed trends in immunisation performance and financing in the DRC from 2002 to 2010. METHODS: The scope of the analysis includes GAVI's total financial support and the value of vaccines and syringes purchased by GAVI for the DRC from 2002 to 2010. Data were collected through a review of published and grey literature and interviews with key stakeholders in the DRC. We assessed the allocation and use of GAVI funds for each of GAVI's support areas, as well as trends in immunisation performance and financing. FINDINGS: DTP3 coverage increased from 2002 (38%) to 2007 (72%) but had decreased to a level below 70% in 2008 (68%) and 2010 (63%). The overall funding for vaccines increased from US$5.4 million in 2006 to US$30.5 million in 2010 (mostly from GAVI support for new vaccines). However, during the same period, the funding from national (government) and international (GAVI and other donors) sources for routine immunisation services (except vaccines) decreased from US$36.4 million to US$24.4 million. This drop in overall funding (33%) primarily affected surveillance, transport, and cold chain equipment. INTERPRETATION: GAVI support to DRC has enhanced significant progress in routine immunisation performance and financing during 2002-2010. Although progress has been partly sustained, the initial observed increase in DTP3 coverage and available funding for routine immunisation halted towards the end of the analysis period, coinciding with tetravalent and pentavalent vaccine introduction. These findings highlight the need for additional efforts to ensure the sustainability of routine immunization program performance and financing.

The Elimination of Haemophilus influenzae type b meningitis following conjugate vaccine introduction in Senegal.

BACKGROUND: Senegal introduced routine infant Haemophilus influenzae type b (Hib) conjugate vaccine during 2005. METHODS: We evaluated acute bacterial meningitis surveillance data among children 0 to 59 months of age collected during January 2003 to September 2007 at the major pediatric referral hospital in the Dakar Region of Senegal. Hib vaccine effectiveness was assessed using a case-control design. RESULTS: A total of 1749 children with suspected bacterial meningitis were included in the current study of whom 142 (8%) had Hib identified. Among children less than age 1 year, the average annual Hib meningitis incidence decreased from 22 to 47 per 100,000 during 2003-2005 to 1.4 per 100,000 during 2007, while pneumococcal meningitis incidence remained stable. Before vaccine introduction, calculated incidences varied over 4-fold between districts within the Dakar Region for the years 2003 to 2005. Following use of Hib vaccine, pneumococcus has now become the most common etiology of pediatric acute bacterial meningitis in Dakar region. CONCLUSIONS: Senegal successfully implemented Hib conjugate vaccine into their routine infant immunization program with a resultant near elimination of Hib meningitis burden.

Study comparing human papillomavirus (HPV) real-time multiplex PCR and Hybrid Capture II INNO-LiPA v2 HPV genotyping PCR assays.

Human papillomavirus (HPV) DNA genotyping is an essential test to establish efficacy in HPV vaccine clinical trials and HPV prevalence in natural history studies. A number of HPV DNA genotyping methods have been cited in the literature, but the comparability of the outcomes from the different methods has not been well characterized. Clinically, cytology is used to establish possible HPV infection. We evaluated the sensitivity and specificity of HPV multiplex PCR assays compared to those of the testing scheme of the Hybrid Capture II (HCII) assay followed by an HPV PCR/line hybridization assay (HCII-LiPA v2). SurePath residual samples were split into two aliquots. One aliquot was subjected to HCII testing followed by DNA extraction and LiPA v2 genotyping. The second aliquot was shipped to a second laboratory, where DNA was extracted and HPV multiplex PCR testing was performed. Comparisons were evaluated for 15 HPV types common in both assays. A slightly higher proportion of samples tested positive by the HPV multiplex PCR than by the HCII-LiPA v2 assay. The sensitivities of the multiplex PCR assay relative to those of the HCII-LiPA v2 assay for HPV types 6, 11, 16, and 18, for example, were 0.806, 0.646, 0.920, and 0.860, respectively; the specificities were 0.986, 0.998, 0.960, and 0.986, respectively. The overall comparability of detection of the 15 HPV types was quite high. Analyses of DNA genotype testing compared to cytology results demonstrated a significant discordance between cytology-negative (normal) and HPV DNA-positive results. This demonstrates the challenges of cytological diagnosis and the possibility that a significant number of HPV-infected cells may appear cytologically normal.

Estimation of the incidence of genital warts and the cost of illness in Germany: a cross-sectional study.

BACKGROUND: Human papillomavirus (HPV) is a necessary cause of cervical cancer. HPV is also responsible for benign condylomata acuminata, also known as genital warts. We assessed the incidence of genital warts in Germany and collected information on their management to estimate the annual cost of disease. METHODS: This was a multi-centre observational (cross-sectional) study of genital warts in Germany. Data were collected from gynecologists, dermatologists, and urologists seeing patients with genital warts between February and April 2005. The number of patients with new and recurrent genital warts was used to estimate the incidence in Germany. We assessed resource use for patients with genital warts seen during a two-month period as well as retrospective resource use twelve months prior to the inclusion visit through a chart review. The mean costs of treatment of patients with genital warts from third-party payer and societal perspectives were estimated, and the total annual cost of genital warts was then calculated. RESULTS: For the incidence calculation 217 specialists provided information on 848 patients and 214 specialists provided resource use data for 617 patients to assess resource consumption. The incidence of new and recurrent cases of genital warts was 113.7 and 34.7 per 100 000, respectively, for women aged 14-65 years consulting gynecologists. The highest incidence was observed in women aged 14-25 years (171.0 per 100 000) for new cases and in women aged 26-45 years (53.1 per 100 000) for recurrent cases. The sample size for males was too small to allow a meaningful estimate of the incidence. The mean direct cost per patient with new genital warts was estimated at 378 euros (95% CI: 310.8-444.9); for recurrent genital warts at 603 euros (95% CI: 436.5-814.5), and for resistant genital warts at 1,142 euros (95% CI: 639.6-1752.3). The overall cost to third-party payers was estimated at 49.0 million euros, and the total societal cost at 54.1 million euros, corresponding to an average cost per patient of 550 euros and 607 euros, respectively. CONCLUSION: The societal burden and costs of managing and treating genital warts in Germany are considerable. A vaccination programme using the quadrivalent human papillomavirus vaccine could provide a substantial health benefit and reduce the costs associated with genital warts in Germany.

[Invasive cervical cancer treatment costs in France]. / Coût de la prise en charge du cancer invasif du col de l'utérus en France.

The objective of this study was to estimate the direct costs of invasive cervical cancer (ICC) management to the French national health insurance system the 1st year after ICC diagnosis. A retrospective survey was conducted in three centres in 2005, including 42 patients admitted for ICC between 2001-2003. Medical records were examined for data relating to treatments and to determine the management costs. To estimate the annual cost of ICC management in France, data were extrapolated to the general population. The number of new ICC cases in France was estimated at 3,247 in 2003. The mean hospitalisation cost increased with ICC severity at diagnosis: 9,164 euros for stage I, 15,999 euros for stage II, 22,697 euros for stage III, and 26,886 euros for stage IV. The annual cost associated with the medical management of ICC patients was estimated at 43,862,125 euros (sensitivity range 32,973,461 euros-54,748,422 euros) corresponding to a mean patient cost of 13,509 euros. Recent HPV vaccination studies have shown 100 % for a quadrivalent (6,11,16,18) HPV vaccine against HPV-induced carcinoma in situ (FIGO stage 0/CIN3), a precursor lesion that may develop into ICC. Thus, it is expected that this vaccine will significantly reduce the socio-economic burden associated with this disease.

Differences in patient and bed partner-assessed quality of life in sleep-disordered breathing.

Sleep-disordered breathing (SDB) is associated with daytime sleepiness and impaired quality of life. Clinical experience suggests that there is a discrepancy between the information provided by the patient and the bed partner. Although this discrepancy is widely recognized, it is not known whether there are differences in quality of life ratings as reported by the patient and by the bed partner on the patient's behalf. Using the Short-Form 36 to assess quality of life in 122 patients with SDB (apnea-hypopnea index > or = 5 events/hour), this study found that patients with SDB generally rate their quality of life higher than their respective bed partners. Systematic differences existed between the two raters in the following Short-Form 36 domains: physical functioning, general health, and vitality. Moreover, male patients reported a higher functional status compared with female patients relative to their respective bed partners. In contrast, no differences were noted between self and bed partner quality of life in normal subjects (n = 15) without SDB (apnea-hypopnea index < 5 events/hour) recruited from the general community. This study suggests that systematic differences exist between patient- and bed partner-assessed quality of life in SDB. Bed partner ratings provide supplemental information on quality of life impairment in SDB.