Adwoa D. Bentsi-Enchill

Estimates of the effectiveness of a whole-cell pertussis vaccine from an outbreak in an immunized population

Pertussis has re-emerged as a public health problem in Canada in recent years, emphasizing concerns about the effectiveness of the currently licensed whole-cell vaccine. Following a 1994 outbreak in Nova Scotia, we conducted a case-control study of 483 children aged < 10 years to assess vaccine effectiveness. Ninety-three percent of children aged 6 months and above had received three or more doses of vaccine, however, only 78% had received age-appropriate immunization. Among children aged 4 years and more, vaccine effectiveness against laboratory-confirmed pertussis was 57% (95% CI, 23-77%) for age-appropriate immunization (five doses) vs partial or no immunization. Vaccine effectiveness increased with increasing number of doses from 25% (95% CI, -58-65%) for three or more doses to 55% (95% CI, -15-83%) for five doses, compared with 0-2 doses.

Global safety of vaccines: strengthening systems for monitoring, management and the role of GACVS.

Vaccines have contributed enormously in reducing the impact of many infectious diseases, and the expanded use of new and existing vaccines provides unprecedented potential for further reducing the global burden of infectious diseases. Yet, as with the deployment of other technologies, their use may also sometimes be associated with undesirable effects that need to be identified rapidly, understood and minimized. In this article, we review the models and systems that have been developed to monitor and respond to concerns regarding vaccine safety and we give illustrative examples of real or perceived vaccine safety issues. The Global Advisory Committee on Vaccine Safety (GACVS) was set up 10 years ago and charged to provide the WHO with independent advice on vaccine safety issues. The role of the GACVS is both to analyze and to interpret reports of the adverse effects of vaccines that impact on global vaccination programs and strategies, and to foster the development of improved surveillance systems to detect any adverse effects of vaccines, particularly in low- and middle-income countries. It also monitors the development of new vaccines during clinical testing and advises on the safe use of vaccines in immunization programs. As success is achieved with reducing the burden of vaccine-preventable diseases, there will be increasing attention focused on potential adverse effects, on the development of effective surveillance systems to detect adverse effects, and on improved methods to manage and control any harmful consequences of vaccination.

An outbreak of severe infections with community-acquired MRSA carrying the Panton-Valentine leukocidin following vaccination.

Background Infections with community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) are emerging worldwide. We investigated an outbreak of severe CA-MRSA infections in children following out-patient vaccination. Methods and Findings We carried out a field investigation after adverse events following immunization (AEFI) were reported. We reviewed the clinical data from all cases. S. aureus recovered from skin infections and from nasal and throat swabs were analyzed by pulse-field gel electrophoresis, multi locus sequence typing, PCR and microarray. In May 2006, nine children presented with AEFI, ranging from fatal toxic shock syndrome, necrotizing soft tissue infection, purulent abscesses, to fever with rash. All had received a vaccination injection in different health centres in one District of Ho Chi Minh City. Eight children had been vaccinated by the same health care worker (HCW). Deficiencies in vaccine quality, storage practices, or preparation and delivery were not found. Infection control practices were insufficient. CA-MRSA was cultured in four children and from nasal and throat swabs from the HCW. Strains from children and HCW were indistinguishable. All carried the Panton-Valentine leukocidine (PVL), the staphylococcal enterotoxin B gene, the gene complex for staphylococcal-cassette-chromosome mec type V, and were sequence type 59. Strain HCM3A is epidemiologically unrelated to a strain of ST59 prevalent in the USA, although they belong to the same lineage. Conclusions We describe an outbreak of infections with CA-MRSA in children, transmitted by an asymptomatic colonized HCW during immunization injection. Consistent adherence to injection practice guidelines is needed to prevent CA-MRSA transmission in both in- and outpatient settings.

Long-term safety assessment of live attenuated tetravalent dengue vaccines: deliberations from a WHO technical consultation.

Dengue is a rapidly growing public health threat with approximately 2.5 billion people estimated to be at risk. Several vaccine candidates are at various stages of pre-clinical and clinical development. Thus far, live dengue vaccine candidates have been administered to several thousands of volunteers and were well-tolerated, with minimal short-term safety effects reported in Phase I and Phase II clinical trials. Based on the natural history of dengue, a theoretical possibility of an increased risk of severe dengue as a consequence of vaccination has been hypothesized but not yet observed. In October 2011, the World Health Organization (WHO) convened a consultation of experts in dengue, vaccine regulation and vaccine safety to review the current scientific evidence regarding safety concerns associated with live attenuated dengue vaccines and, in particular, to consider methodological approaches for their long-term evaluation. In this paper we summarize the scientific background and methodological considerations relevant to the safety assessment of these vaccines. Careful planning and a coordinated approach to safety assessment are recommended to ensure adequate long-term evaluation of dengue vaccines that will support their introduction and continued use.

Guidelines for collection, analysis and presentation of vaccine safety data in pre-and post-licensure clinical studies

Jan Bonhoeffer, Adwoa Bentsi-Enchill, Robert T. Chen, Margaret C. Fisher, Michael S. Gold, Katharina Hartman, Ulrich Heininger, Bernard Hoet, Thomas Jefferson, Najwa Khuri-Bulos, Katrin S. Kohl, S. Michael Marcy, David Nalin, Robert Pless, Hernan Sanabria-Rojas, Karen Sleeman, Robert Wise and The Brighton Collaboration Methods Working Group

Typhoid fever vaccination strategies.

Typhoid vaccination is an important component of typhoid fever prevention and control, and is recommended for public health programmatic use in both endemic and outbreak settings. We reviewed experiences with various vaccination strategies using the currently available typhoid vaccines (injectable Vi polysaccharide vaccine [ViPS], oral Ty21a vaccine, and injectable typhoid conjugate vaccine [TCV]). We assessed the rationale, acceptability, effectiveness, impact and implementation lessons of these strategies to inform effective typhoid vaccination strategies for the future. Vaccination strategies were categorized by vaccine disease control strategy (preemptive use for endemic disease or to prevent an outbreak, and reactive use for outbreak control) and vaccine delivery strategy (community-based routine, community-based campaign and school-based). Almost all public health typhoid vaccination programs used ViPS vaccine and have been in countries of Asia, with one example in the Pacific and one experience using the Ty21a vaccine in South America. All vaccination strategies were found to be acceptable, feasible and effective in the settings evaluated; evidence of impact, where available, was strongest in endemic settings and in the short- to medium-term. Vaccination was cost-effective in high-incidence but not low-incidence settings. Experience in disaster and outbreak settings remains limited. TCVs have recently become available and none are WHO-prequalified yet; no program experience with TCVs was found in published literature. Despite the demonstrated success of several typhoid vaccination strategies, typhoid vaccines remain underused. Implementation lessons should be applied to design optimal vaccination strategies using TCVs which have several anticipated advantages, such as potential for use in infant immunization programs and longer duration of protection, over the ViPS and Ty21a vaccines for typhoid prevention and control.

Guidelines for collection, analysis and presentation of vaccine safety data in surveillance systems

Jan Bonhoeffer, Adwoa Bentsi-Enchill, Robert T. Chen, Margaret C. Fisher, Michael S. Gold, Katharina Hartman, Ulrich Heininger, Bernard Hoet, Thomas Jefferson, Najwa Khuri-Bulos, Katrin Kohl, S. Michael Marcy, David Nalin, Robert Pless, Hernan Sanabria-Rojas, Karen Sleeman, Robert Wise and The Brighton Collaboration Methods Working Group

Viscerotropic disease: Case definition and guidelines for collection, analysis, and presentation of immunization safety data

iscerotropic disease: Case definition and guidelines for collection, analysis, and resentation of immunization safety data ark D. Gershmana,∗, J. Erin Staplesb, Adwoa D. Bentsi-Enchill c, J. Gabrielle Breugelmansd, lacus S. Britoe, Luiz Antonio Bastos Camachof, Pascale Cotting, Cristina Domingoh, Anna Durbin i, oaquim Gasconj, Fouzia Guenanechek,1, Edward B. Hayes j, Zsuzsanna Jelenik l, Alena Khromavam, einaldo de Menezes Martinsn, Mario Masana Wilsono,2, Nathalie Massyp, Abdulsalami Nasidiq, atthias Niedrigh, Adam Sherwatr,3, Theodore Tsai s, Anna Vilella j, Mary Elizabeth Wilsont, atrin S. Kohla , The Brighton Collaboration Viscerotropic Disease Working Group

Monitoring Vaccine Safety during Measles Mass Immunization Campaigns: Clinical and Programmatic Issues

In the planning and implementation of mass immunization campaigns, vaccine delivery has always been a priority. However, safety issues have gained increasingly more attention and grown in importance, and campaign planners must now take them into prime consideration. The World Health Organization has released guidelines to assist with the design and implementation of safety surveillance systems, primarily for developing countries, and these include a new monograph for measles mass campaigns. Experience in the past decade with mass campaigns (primarily in developed countries) shows that measles vaccine performs in these settings as anticipated from pre- and post-licensure studies. Serious adverse events are rare, even under the increased scrutiny extended during a campaign. The experience in developing country settings is growing. The implementation of safety surveillance for mass campaigns offers a unique opportunity for countries to avoid crisis situations and to begin vaccine safety monitoring in routine immunization programs.

A Turning Point in Typhoid Control.

The highest burden of morbidity and mortality associated with Salmonella enterica serovar Typhi and S. enterica serovar Paratyphi A occurs in South and Southeast Asia and in sub-Saharan Africa. In the last 2 decades, significant contributions to our overall understanding of typhoid fever and paratyphoid fever (collectively enteric fever) have been achieved through key population-based disease burden studies. Of particular note, the landmark Diseases of the Most Impoverished (DOMI) project, conducted between 2000 and 2008, documented the high incidence of blood culture–confirmed typhoid and several epidemiological aspects of the disease in 7 Asian countries [1]. Similarly, the Typhoid Surveillance in Africa Program, conducted in 13 countries in sub-Saharan Africa between 2010 and 2014, generated significant data to fill the knowledge gaps on typhoid fever and nontyphoidal Salmonella disease in that geographic region [2]. Despite these large multicountry studies, and other single-country studies published in recent decades, several epidemiological gaps remain. Several current population studies are anticipated to add to the growing body of knowledge on all 3 invasive Salmonella diseases that will make major contributions to their effective control [3–6]. In this supplement, the Surveillance for Enteric Fever in Asia Project (SEAP), a multicountry study covering Bangladesh, India, Nepal, and Pakistan, reports data from a retrospective records review of enteric fever in Phase I of the study [3]. The site-specific findings reported in this supplement [7–10] confirm that enteric fever remains an important public health burden in the region a decade after the DOMI study. These SEAP Phase I reports and, importantly, future results from the prospective studies in Phase II will be invaluable in guiding control strategies for typhoid and paratyphoid fever in Asia. The experience in Bangladesh illustrates opportunities for leveraging existing surveillance approaches and resources where possible [8]. Andrews et al report a low blood culture positivity rate of 4.1% among clinically diagnosed enteric fever cases [7], reinforcing the poor reliability of clinical diagnosis and, conversely, the importance of strengthening surveillance for blood culture confirmation in all typhoidand paratyphoid-endemic countries. Furthermore, Antillon et al in their systematic review report a blood culture diagnostic sensitivity of 0.59 (95% confidence interval, .54–.64) and found a significant “but modest” relationship between blood volume and blood culture sensitivity, irrespective of patient age, prior antimicrobial use, or other potential confounders [11]. These reports are an important addition to the understanding of diagnostic sensitivity and will allow key adjustments to be made in enteric fever burden estimation. All participating sites report data on antimicrobial resistance, which are key considerations for countries conducting enteric fever surveillance given the alarming trends in antibiotic resistance, including the recent discovery of an extensively drug-resistant (XDR) Salmonella Typhi strain that caused a typhoid fever outbreak in Sindh Province, Pakistan. The emergence of that XDR strain, which has been described as encoding resistance to all the major antimicrobials that have been routinely used for treating typhoid fever over the last 7 decades, amplifies the urgent concerns about narrowing therapeutic options for treatment and control of typhoid fever, and a real need for culture and antimicrobial sensitivity to guide treatment of typhoid fever [12, 13]. Kaljee et al provide critical insights on community and patient perceptions and other socioeconomic factors underlying healthcare utilization patterns in Nepal [14]. We encourage typhoid researchers and endemic countries to gather such data as an important contribution to interpreting epidemiological data and designing effective control strategies. In his supplement article, Luby presents a compelling discussion on the challenges of short-term to medium-term strategies for typhoid control focused on improvements in water and sanitation and the potential value of combined vaccination and E D I T O R I A L C O M M E N T A R Y