WHAT'S NEW THIS THURSDAY; ZIMBABWE'S CASE BASED MEASLES SURVEILLANCE

Tuesday, 31st of January 2012

• ZIMBABWE’S CASE BASED MEASLES SURVEILLANCE

From the Pan African Medical Journal:

http://www.panafrican-med-journal.com/content/article/11/2/full/

Regis Choto, Addmore Chadambuka, Gerald Shambira, Notion Gombe, Mufuta Tshimanga, Stanley Midzi, Joseph Mberikunashe. Trends in Performance of the National Measles Case-Based Surveillance System, Ministry of Health and Child Welfare, Zimbabwe (1999 - 2008).
The Pan African Medical Journal. 2012;11:2

Key words: Diseases surveillance, active surveillance, indicators, Measles, Zimbabwe

Permanent link: http://www.panafrican-med-journal.com/content/article/11/2/full

Received: 30/03/2011 - Accepted: 25/10/2011 - Published: 11/01/2012

© Regis Choto et al.� � The Pan African Medical Journal - ISSN 1937-8688. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. �

• 
  Trends in Performance of the National Measles Case-Based Surveillance System, Ministry of Health and Child Welfare, Zimbabwe (1999 - 2008)
  �
  Regis Choto1, Addmore Chadambuka1, Gerald Shambira1, Notion Gombe1, Mufuta Tshimanga1, Stanley Midzi2, Joseph Mberikunashe2
  �
  1MPH Programme, Department of Community Medicine, University of Zimbabwe, Zimbabwe, 2Department of Epidemiology and Disease Control, Ministry of Health and Child Welfare, Harare, Zimbabwe
  �
  �
  &Corresponding author
  Chadambuka Addmore, Health Studies Office P.O. Box CY 1122 Causeway Harare, Zimbabwe
  �
  �
  Introduction
  Public health surveillance has been defined as the ongoing, systematic collection, analysis, interpretation and dissemination of data regarding a health related event for use in public health action to reduce mortality and to improve health [1-3]. Data generated from such public health surveillance systems is used for guiding immediate public health action, program planning and evaluation, monitor trends in the burden of disease and formulating research hypotheses. As an essential to public health action and for surveillance purposes, the public health information systems involved need to include a variety of data sources [4]. These systems vary from a simple system collecting data from a single source to electronic systems that receive data from many sources in multiple formats, to complex surveys. The number and variety of systems, will likely increase with advances in electronic data interchange, and integration of data which will also heighten the importance of patient privacy, data confidentiality and system security. To ensure that problems of public health importance are monitored effectively and efficiently, periodic evaluations of public health surveillance systems are critical. Despite achieving and sustaining global measles vaccination coverage of about 80% over the past decade, worldwide measles remains the fifth leading cause of mortality among children aged less than 5 years [5]. It accounts for more than 30 million cases annually and 0.9 million deaths every year, with approximately half of these occurring in Africa [6]. Measles is vaccine preventable and a child is eligible for measles vaccine once they attain nine months of age. Measles is one of the diseases earmarked for elimination worldwide. In line with the WHO pre-elimination goal for measles, the WHO African Region recommended to its member countries the measles case based surveillance with laboratory confirmation as one of the main strategies for measles control. Under this case based surveillance system, every measles case is reported and investigated immediately and also included in weekly reporting system. In countries where the main objective is to completely interrupt measles transmission, an intensive case-based surveillance to detect, investigate and confirm every suspected measles case in the community is recommended. To achieve measles pre-elimination, a high routine vaccine coverage rate (with at least 90% of infants in all regions needing vaccination before their first birthday) and periodic vaccination supplemental immunization activities (reaching at least 95% of the targeted population) are required. The periodicity of supplemental immunization activities (SIAs) though routinely coming every 3 to 4 years, is determined by the routine EPI coverage, the coverage during catch up SIAs and the results of measles surveillance.
  �
  Measles elimination is defined as the absence of endemic measles cases for a period of twelve months or more, in the presence of adequate surveillance, and when the following criteria are met: (i) achieving and maintaining at least 95% coverage with both first dose measles vaccination and the second opportunity of measles vaccination in all districts and nationally; (ii) having less than 10 confirmed cases in 80% or more of measles outbreaks; (iii) achieving a measles incidence of < 1 confirmed measles case per million population per year [7]. In Zimbabwe, measles surveillance is in the elimination phase and as such a measles case-based surveillance system was adopted since 1998, with objectives to identify at risk populations; monitor impact of routine and supplementary immunization activities; measure progress towards achieving elimination of measles and monitor accumulation of susceptible populations and take appropriate action. In line with the WHO AFRO regional strategy, Zimbabwe commenced supplemental immunization activities in 1998 with follow up SIAs being done in 2002, 2006, and 2009. These SIAs were targeting children 9 months to 14 years in catch-up campaigns and 9 months to 5 years during periodic follow-up campaigns.
  �
  Since the adoption of the measles case-based surveillance system in 1998, in Zimbabwe, data has been routinely collected at all levels of the health delivery system and sent to the national level. To our knowledge there was no documented evidence to show data collected was periodically being used to identify at risk populations, monitor impact of interventions and measure progress towards achieving measles elimination. We analysed this data to determine trends in performance of the national measles case-based surveillance system and advise policy.
  �
  �
  �
  Methods
  Surveillance system
  �
  In Zimbabwe, surveillance data for suspected measles cases is routinely collected at all levels of the health delivery system using the measles case based surveillance form and sent to MOHCW Head Office. Data from the primary facilities is sent through the district, province onto national level where it is entered into the measles case-based surveillance system database, (EPI INFO based), where it is consolidated, cleaned, analyzed and disseminated for action. A copy of this database is also shared with the World Health Organisation.
  �
  Important variables captured by the dataset include; patient's name, age, sex, vaccination status, area of residence (by province, district), date of rash onset, date of first investigation (notification, specimen collection and specimen sending), dates of specimen arrival and dispatch of results from the national virology laboratory, specimen condition on arrival at national virology laboratory, Measles IgM test result, Rubella IgM test and final case classification. Feedback of the final case classification is given to the reporting facility through the same channel used for reporting.
  �
  Surveillance Methods
  �
  We conducted a retrospective record review of the national measles case-based surveillance dataset for the period 1999 to 2008, assessing for trends in proportion of investigated cases; timeliness and nature of specimens received at laboratory; timeliness of feedback of serology results, proportion of cases confirmed as measles and national annualized rates of investigation. Comparisons with WHO recommended performance indicators (Table 1) to determine quality of measles surveillance were done and secondary data analysis was done after cleaning, using Microsoft Excel and Epi-Info to generate frequencies and proportions.
  �
  Permission to proceed with the study was obtained from the Director of Epidemiology and Disease Control, Ministry of Health and Child Welfare and Health Studies Office. Ethical clearance was obtained from Medical Research Council of Zimbabwe. Names of patients and addresses were omitted from the analysis. Confidentiality was assured and maintained.
  �
  �
  Results
  Cumulatively 4994 suspected measles cases were reported and investigated for the period January 1999 to December 2008. Out of these, 200 cases (4.0%) had their records duplicated, which resulted in a 4.4% over estimation of reported cases. Among the 4994 cases investigated, the 1 - 4 year and 5 - 14 year age groups were the most affected accounting for 1173 (23.5%) and 2 668 (53.4%) of the cases respectively. The minority of reported cases came from the below 1 year and above 15 years age groups which accounted for 157 (3.1%) and 116 (2.3%) cases respectively. One hundred and three cases (18.1%) of the total reported cases had missing information on age group.
  �
  The proportion of males and females among the cases reported for the period 1999 - 2008 was almost similar with a male to female distribution ratio of (2306: 2184) of 1:1. Five hundred and four cases (10.1%) had missing information on gender status. Fifty percent (2579 cases) of the overall suspected cases investigated had received at least a single dose of measles vaccine and a very small proportion 0.5% (24 cases) had not received any measles vaccination before. However, 2139 cases (42.8%) had missing information on vaccination status. Out of the 4994 cumulative suspected measles cases reported, 150 cases were confirmed as measles and of these, 5 cases (3.3%) had not been vaccinated before and 53 cases (35.3%) had at least received a single dose of the measles vaccine. The remaining 71 cases (51.3%) had missing information on vaccination status.
  �
  Despite three supplemental immunization activities (SIAs) being carried out in Zimbabwe during the period 1999 - 2008, routine measles coverage has been declining according to WHO published estimates for the same period. This has been coupled with a decline in yearly reported suspected measles cases with exceptions recorded in the years 2000 and 2004. The proportion of investigated cases among the suspected for the same period however improved with at least 90% of cases investigated yearly (Figure 1).
  �
  Characterization of specimens received at the laboratory yearly during the period under review revealed that the proportion of specimens arriving at the laboratory timely (within 3 days of being taken) was consistently below the WHO recommended target of 80% in the period 1999 - 2008 with the exception of 2008. The proportion of serum specimens arriving at the national measles virology laboratory in good condition during the period 2004 - 2008 was below the WHO recommended target of 90 % except for the years 2005 and 2008. For the period 1999 - 2003, no data was captured on nature of specimens that were being collected and sent to the laboratory. The proportion of specimens received at the laboratory with results sent to the national level timely (within 7 days of specimen reciept at the laboratory) was below the recommended WHO target of 80% throughout 1999 - 2008. However, a general increase in proportion of specimens with results sent out timely from the laboratory was noted in the period 1999 - 2005. This was followed by a decline in the period 2005 - 2007 and then an increase in 2008 (Table 2).
  �
  The proportion of investigated cases confirmed to be measles by serological investigation were within the WHO recommended target of less than 10%, during the period 1999 - 2008 except in 2003. The majority of investigated cases were confirmed to be rubella, a differential diagnosis of measles, with proportions ranging between 12 - 40%, during the period 1999 - 2008.
  �
  Overall, the national measles surveillance system performed very well for the period 1999 - 2008, having an average annualized rate of investigation of 4 cases per 100 000 per year. On disaggregation of rates of case investigation per province on average, Matabeleland South and Matabeleland North Provinces performed extremely well in case investigation compared to the other provinces, while on the other hand Bulawayo Province performed badly (Figure 2).
  �
  On further analysis of the performance of the national measles case based surveillance system in terms of case investigation by year, there was generally a declining trend in the national annualized rates of investigation which decreased from 9.04 cases per 100,000 population per year in 2000 to 1.58 cases/100,000 population per year in 2008. The national surveillance system performed below the recommended WHO target of 2 cases/100,000 population per year for the period 2006 - 2008 (Figure 3).
  �
  �
  Discussion
  Despite limitations in the nature of study design in that we were relying on already collected data and could not come up with definitive reasons as to why there were certain trends and anomalies in our findings, our study revealed a number of important findings. These were relating to quality of data collected by the surveillance system, populations still at risk of contracting measles in Zimbabwe and how the national measles case- based surveillance system has been performing in the period under review.
  �
  A significant proportion of the data had duplications and a small proportion had missing information on important variables (i.e. demographics and vaccination status) which made meaningful review of some of these records difficult. This is an indication of important gaps in the data collection system which needs urgent redress if reliable data interpretation is to be achieved and properly guided sound health policies are to be made based on the true picture on the ground. According to the Centre for Disease Control updated guidelines for evaluation of public health surveillance systems of 2001, quality of data is cited to be influenced by the performance of the screening and diagnostic tests (i.e. case definition) for the health-related event, the clarity of hardcopy or electronic surveillance forms, the quality of training and supervision of persons who complete these surveillance forms, and the care exercised in data management [9].
  �
  This study demonstrated that most affected age groups were the under 15 years, with 53.4% of them being children between the ages of 5 - 14 years, while the under 1 year and the above 15 year olds constituted the minority of cases. Similar observations were noted in other African countries in which an average 50% of cases occur in children aged 5 - 14 years [10].
  �
  This highlights the fact that the 9 months - 15 year age group still remains a risky population for contracting measles in Zimbabwe and interventions like immunization campaigns need to be targeted at this group if morbidity and mortality due to measles are to be drastically reduced. In surveys carried out by the WHO in Malawi, mass campaign targeting of the 9 months - 14 years age group was noted to reduce measles morbidity and mortality to near zero [11].
  �
  Overall, reported suspected and confirmed measles cases has been declining for the period 1999 - 2008 which may be attributed to among other things the successful EPI and Vitamin A supplementation as reported yearly by the MOHCW [12]. Discrepancies noted in the general declining trend in reported suspected and confirmed measles cases for the years 2000 and 2004, may be attributed to measles outbreaks that were reported in the same years in Zimbabwe. During these outbreaks, due to the overwhelming number of cases reported most cases i.e. suspected or probable could have been done on clinical basis which may also explain the sharp increase in cases reported.
  �
  Declining reported cases may also be reflective of the deteriorating health delivery that the country has been experiencing since the year 2000 [13-14], which may be resulting in reduced capacity to detect and confirm measles cases. The associated decline in annualized rates of investigation noted since the year 2000 further supports the fact that health personnel were not doing enough in terms of actively investigating for suspected measles cases. This may have resulted in under reporting of a significant amount of cases. This is consistent with findings noted by the World Health Organisation in its proposal to respond to and control the ongoing measles outbreak in Zimbabwe in 2009, in which socio-economic challenges which were resulting in high staff attrition, closure of health facilities, shortages in gas supply impacting on cold chain functionality, lack of fuel & vehicles shortages were noted as major contributors to the decline in routine immunization coverage [13-15].
  �
  Challenges in maintaining the reverse cold chain (as suggested by a significant proportion of specimens arriving at the laboratory in bad condition) and communication and transport challenges (as suggested by a significant proportion of specimens failing to meet set timeframes in collection, receipt at the laboratory and feedback of results) may also explain why sensitivity of the system is low or on the decline. In an evaluation done by Chadambuka et al (2006) in Mberengwa, similar contributing factors were cited as reasons for poor performance of the measles case based surveillance system in that district [16].
  �
  �
  �
  Conclusion
  The national measles case based surveillance system improved in timeliness and feedback but its sensitivity declined due to reduced capacity to detect and confirm measles. The system has been operating below the recommended WHO standards. Data quality has on the overall been poor.
  �
  Recommendations We recommended that regular training and refresher courses be organized on EPI surveillance to improve health staff's knowledge of the system and hence the system's performance. There is need to conduct periodic reviews of provincial EPI surveillance data in order to strengthen weak districts. More research to determine why some provinces/districts are continually performing poorly should be facilitated.
  �
  �
  Acknowledgments
  We would like to acknowledge the support we got from the Director of Epidemiology and Disease Control in the Ministry of Health and Child Welfare who gave us permission to analyze this dataset.
  �
  �
  Competing interests
  The authors declare no competing interests.
  �
  �
  Authors’ contribution
  Regis C. Choto: He was responsible for the conception of the problem, design, collection, analysis and interpretation of data and drafting the final article. Addmore Chadambuka: Participated in the design, analysis and interpretation of data and drafting the final article and critical review of the final draft. Gerald Shambira: He was responsible for the conception of the problem, design, analysis and interpretation of data and drafting the final article. Notion T. Gombe: He was responsible for the conception of the problem, design, collection, analysis and interpretation of data and drafting the final article. Mufuta Tshimanga: Had oversight of all the stages of the research. Critically reviewed the final draft for academic content Stanley M. Midzi: He was responsible for the design, analysis and interpretation of data and drafting the final article. Joseph Mberikunashe: He was responsible for the design, analysis and interpretation of data and drafting the final article.
  �
  �  
• RECOMBINANT SIMIAN ADENOVIRUS AS A POTENT VACCINE VECTOR

1. J Infect Dis. (2012) doi: 10.1093/infdis/jir850 First published online: January 24, 2012

Best viewed at http://jid.oxfordjournals.org/content/early/2012/01/24/infdis.jir850.full

Clinical Assessment of a Recombinant Simian Adenovirus ChAd63: A Potent New Vaccine Vector

1. 1.� � Geraldine A. O'Hara1,^a,
2. 2.� � Christopher J. A. Duncan1,^a,
3. 3.� � Katie J. Ewer1,^a,
4. 4.� � Katharine A. Collins1,
5. 5.� � Sean C. Elias1,
6. 6.� � Fenella D. Halstead1,
7. 7.� � Anna L. Goodman1,
8. 8.� � Nick J. Edwards1,
9. 9.� � Arturo Reyes-Sandoval1,

10. Prudence Bird2,

11. Rosalind Rowland1,

12. Susanne H. Sheehy1,

13. Ian D. Poulton1,

14. Claire Hutchings1,

15. Stephen Todryk1,

16. Laura Andrews1,

17. Antonella Folgori1,

18. Eleanor Berrie2,

19. Sarah Moyle2,

20. Alfredo Nicosia3,4,

21. Stefano Colloca3,

22. Riccardo Cortese3,4,

23. Loredana Siani3,

24. Alison M. Lawrie1,

25. Sarah C. Gilbert1 and

26. Adrian V. S. Hill1

+ Author Affiliations

1. 1.� � � ¹Centre for Clinical Vaccinology and Tropical Medicine and the Jenner Institute Laboratories, University of Oxford
2. 2.� � � ²Clinical BioManufacturing Facility, Nuffield Department of Clinical Medicine, Churchill Hospital, University of Oxford, Headington, United Kingdom
3. 3.� � � ³Okairos AG, Rome
4. 4.� � � ⁴CEINGE, Naples, Italy
5. Correspondence: Geraldine O’Hara, MB ChB, Centre for Clinical Vaccinology and Tropical Medicine, Churchill Hospital, Old Rd, Headington, Oxford OX3 7LJ, UK (geraldine.ohara@ndm.ox.ac.uk).

�

Abstract

Background. Vaccine development in human Plasmodium falciparum malaria has been hampered by the exceptionally high levels of CD8⁺ T cells required for efficacy. Use of potently immunogenic human adenoviruses as vaccine vectors could overcome this problem, but these are limited by preexisting immunity to human adenoviruses.

Methods. From 2007 to 2010, we undertook a phase I dose and route finding study of a new malaria vaccine, a replication-incompetent chimpanzee adenovirus 63 (ChAd63) encoding the preerythrocytic insert multiple epitope thrombospondin-related adhesion protein (ME-TRAP; n = 54 vaccinees) administered alone (n = 28) or with a modified vaccinia virus Ankara (MVA) ME-TRAP booster immunization 8 weeks later (n = 26). We observed an excellent safety profile. High levels of TRAP antigen–specific CD8⁺ and CD4⁺ T cells, as detected by interferon γ enzyme-linked immunospot assay and flow cytometry, were induced by intramuscular ChAd63 ME-TRAP immunization at doses of 5 × 10¹⁰ viral particles and above. Subsequent administration of MVA ME-TRAP boosted responses to exceptionally high levels, and responses were maintained for up to 30 months postvaccination.

Conclusions. The ChAd63 chimpanzee adenovirus vector appears safe and highly immunogenic, providing a viable alternative to human adenoviruses as vaccine vectors for human use.

Clinical Trials Registration. NCT00890019.

The induction of potent cellular immunity remains a central difficulty in vaccinology. Malaria is a disease widely regarded as an important potential target of improved T-cell–inducing vaccines. A method of immunoprophylaxis, such as a vaccine, would offer a valuable tool against both the morbidity and mortality caused by malaria [1]. Immunization of mice with irradiated sporozoites of murine Plasmodium falciparum provides protection against later challenge with murine malaria, and by transferring the CD8⁺ T lymphocyte clones specific to malaria surface antigens nonimmune mice can be protected [2–4]. High-level protective CD8⁺ T-cell responses can be induced by many vaccine types in small animals, but despite numerous attempts, there is no clear demonstration of the induction of very potent CD8⁺ T-cell responses in humans [5–7]. In animal models, such high levels are often required to induce protective immunity [8].

Of the vaccination approaches assessed for induction of cellular immunity in humans, adenoviral vectors and heterologous prime-boost approaches have shown the most promise [9]. A series of phase I/IIa clinical studies at the University of Oxford have assessed prime-boost immunization strategies in healthy, malaria-naive adult human volunteers using plasmid DNA and the poxviruses modified vaccinia virus Ankara (MVA) and FP9 as vectors [7]. The most protective antigenic insert tested in these vectors was the T-cell multiple epitope string fused to the thrombospondin-related adhesion protein (ME-TRAP), which was more protective than the circumsporozoite protein or a polyprotein insert [7]. TRAP is a surface protein from the sporozoite stage of P. falciparum [10]. Several immunization regimes using these vectors with the ME-TRAP insert led to statistically significant delays in time to patent parasitemia, reflecting 80%–92% reductions in liver-stage parasite numbers emerging from the liver after experimental malaria infections [11]. However, these regimes induced predominantly CD4⁺ T-cell responses, and although T-cell responses correlated with vaccine efficacy, these approaches failed to induce protective immunity in the majority of vaccinees, suggesting a need for more potent vectors such as adenoviruses.

Adenoviral vectors suffered a setback with the failed human immunodeficiency virus type 1 (HIV-1) STEP vaccine trial, which showed a lack of efficacy and a nonsignificant trend toward increased HIV-1 infection in vaccinees [12]. However, antigen-specific responses in that trial were only of the order of 300 spot-forming cells (SFC) per million peripheral blood mononuclear cells (PBMCs), probably in part explaining the lack of efficacy. Moreover, the possibility that antivector immunity might have contributed to the suggested safety concern in the STEP trial has led to renewed interest in the use of nonhuman adenoviral vectors for several diseases [7].

Estimates suggest that, depending on the region, between 45% and 80 % of adults carry AdHu5 neutralizing antibodies (nAb) [13]. Simian adenoviruses are not known to cause pathological illness in humans, and the prevalence of antibodies to chimpanzee-origin adenoviruses is <5% in humans residing in the United States. Prevalence in young children in Kenya, a target group for a malaria vaccine, is low, with only 4% of 1–6-year-old children in one study having high-titer nAb to chimpanzee adenovirus 63 (ChAd63), compared with 23% having high-titer nAb to AdHu5 [14]. When used in preclinical models, some simian adenoviruses showed similar levels of immunogenicity to the very potent human adenovirus AdHu5. In the preclinical P. berghei model, some simian adenoviruses were comparable to or appeared better than AdHu5 in terms of immunogenicity and protective efficacy; and in macaques, good T-cell immunogenicity was observed [15, 16].

Here, to our knowledge, we report the first-in-human clinical experience of a highly immunogenic nonhuman adenovirus vaccine vector.

Previous SectionNext Section

STUDY DESIGN

This was an open-label phase I dose and route finding study from October 2007 to May 2010 to evaluate the safety and immunogenicity of ChAd63 ME-TRAP alone, and in a prime-boost regimen with MVA ME-TRAP. Participant flow and study design is summarized in Figure 1, and the vaccination regimens for each group are shown in Supplementary figure 1A and 1B.

View larger version:

� � � � � � In this page

� � � � � � In a new window

� � � � � � Download as PowerPoint Slide

Figure 1.

CONSORT chart.

Abbreviations: ChAd63, chimpanzee adenovirus; i.d., intradermal; i.m., intramuscular; MVA, modified vaccinia virus Ankara.

The dose of ChAd63 ME-TRAP was first escalated from 1 × 10⁸ to 5 × 10¹⁰ viral particles (vp) by the intradermal route (groups 1–4, n = 8 per group), then from 1 × 10¹⁰ to 2 × 10¹¹ vp by the intramuscular route (groups 5–7, n = 4–10 per group; see Figure 1). Within these groups, 4 volunteers received a single immunization with ChAd63 ME-TRAP (“A” subgroups, n = 28), and 4 received ChAd63 ME-TRAP followed by MVA ME-TRAP 8 weeks later (“B” subgroups, n = 20). In the highest-dose group (2 × 10¹¹ vp, group 7), 2 volunteers were boosted with intradermal MVA ME-TRAP 2 × 10⁸ plaque-forming units (PFU; group 7B), and 4 volunteers were boosted with intramuscular MVA ME-TRAP 2 × 10⁸ PFU (group 7C).

In addition, in May 2010, all volunteers in the prime-boost groups (n = 26) were invited to return for a late-boosting immunization with either ChAd63 ME-TRAP (5 × 10¹⁰ vp) or MVA ME-TRAP (2 × 10⁸ PFU) intramuscularly. In total, 11 of 26 eligible volunteers were screened for a third immunization and enrolled between June and July 2010. This group was termed group 8. Vaccine allocation was randomized 1:1, stratified by time interval since the last immunization (n = 5 ChAd63 ME-TRAP; n = 6 MVA ME-TRAP). Data for days 21–28 following reboost are presented.

Previous SectionNext Section

RESULTS

Manufacturing Yield and Genetic Stability of ChAd63 ME-TRAP

The Clinical BioManufacturing Facility at the University of Oxford manufactured ChAd63 ME-TRAP [24] with high yield, producing approximately 3.7 × 10¹⁴ vp from a single-bulk cell culture preparation. This was the yield obtained following cell lysis, disaggregation, centrifugation, and filtration. From 2 bulk harvest lots, 12 840 doses of ChAd63 ME-TRAP, with 1 × 10¹¹ vp per vial, were produced.

Genetic stability of ChAd63 ME-TRAP was tested by performing 8 passages of a batch of the virus in human embryonic kidney 293 (HEK293) cells and characterizing the resulting virus using a combination of polymerase chain reaction (PCR) and sequencing. No evidence of genetic instability was detected in either the passaged material or the clinical batch used in the clinical trial.

Safety

There were no serious adverse events. The 417 adverse events considered possibly, probably, or definitely related to vaccination were reported up to and including 28 days post ChAd63 ME-TRAP (184 local and 233 systemic). Local adverse events included pain, redness, swelling, scaling, itching, and warmth. Systemic symptoms solicited using diary cards included fever, feverishness (the sensation of fever without measurable pyrexia), malaise, fatigue, arthralgia, myalgia, headache, and nausea or vomiting. Over 90% of adverse events were mild in nature. A detailed breakdown of adverse events occurring postvaccination can be found in Supplementary figure 1G–K.

All subjects receiving ChAd63 ME-TRAP intradermally (groups 1–4) reported a local adverse event, most commonly redness (100%) and swelling (100%). Incidence of local adverse events was lower in those receiving intramuscular ChAd63 ME-TRAP (groups 5–7), with significantly fewer local adverse events reported per volunteer at comparable doses (P < .005; Figure 2A and 2B).

View larger version:

� � � � � � In this page

� � � � � � In a new window

� � � � � � Download as PowerPoint Slide

Figure 2.

Adverse events. Local and systemic adverse events occurring post ChAd63 ME-TRAP (A–D) and MVA ME-TRAP (B and D). Median and interquartile range number of local (A) and systemic (C) adverse events reported per volunteer post ChAd63 ME-TRAP at different doses and routes. Panels B and D show percentage of volunteers reporting at least 1 local or systemic adverse event; shading indicates severity (highest severity of adverse events reported by volunteers is presented). (*P < .05; ***P < .001; analyzed by Kruskal-Wallis test with Dunn post test.)

Abbreviations: ChAd63, chimpanzee adenovirus; i.d., intradermal; ME-TRAP, multiple epitope-thrombospondin–related adhesion protein; MVA, modified vaccinia virus Ankara.

The most common systemic adverse events occurring were fatigue (87% of volunteers), malaise (69%), and feverishness (54%). In total, 69% of systemic adverse events were reported in the first 48 hours postvaccination, and 64% resolved in this timeframe. The median number of systemic adverse events experienced by a volunteer increased with vaccine dose regardless of route of administration (Figure 2C). In parallel, severity of reported systemic adverse events increased as the dose of ChAd63 ME-TRAP increased. There were 8 individual severe adverse events reported, 4 of which (feverishness, headache, malaise, and coryzal symptoms) occurred in the same volunteer who developed a coryzal illness 13 days postvaccination. Two other volunteers had 24 hours of symptoms immediately post vaccination (1 subject with coryzal symptoms and 1 with myalgia/arthralgia/feverishness).

The safety profile of MVA ME-TRAP was very similar to that reported previously (Figure 2B and 2D) [17, 18]. The preceding dose of ChAd63 ME-TRAP did not affect the intensity or duration of adverse events post-MVA ME-TRAP (data not shown). A similar acceptable safety profile was observed after the reboosting immunizations.

Immunization-related laboratory adverse events resolved in 4 of 54 volunteers following ChAd63 ME-TRAP (2 ALT elevations [<1.5 × upper limit of normal], 1 eosinophilia, and grade 1 thrombocytopenia) and 1 of 26 volunteers following MVA ME-TRAP (grade 1 thrombocytopenia).

Immunogenicity

ELISPOT Responses

Ex vivo interferon γ (IFN-γ) enzyme-linked immunospot (ELISPOT) responses to the vaccine antigen were detectable in all groups after the priming vaccination with ChAd63 ME-TRAP (Figure 3). Unless stated otherwise, values reported represent total summed responses to TRAP pools and ME from the T9/96 P. falciparum strain. No significant difference between doses of ChAd63 ME-TRAP administered via the intramuscular and intradermal different routes was observed (Figure 3A), so these routes were pooled for further analysis.

View larger version:

� � � � � � In this page

� � � � � � In a new window

� � � � � � Download as PowerPoint Slide

Figure 3.

ELISPOT assays. A, Comparison of median ELISPOT responses at comparable doses via intradermal and intramuscular routes. Error bars represent interquartile ranges (IQRs); no significant differences were observed. B and C, Median ELISPOT responses postvaccination in A groups and B groups. D and E, Median ELISPOT responses day 14 and day 63 grouped by priming dose ChAd63 ME-TRAP; error bars represent IQRs. F, Peak median ELISPOT response by priming dose ChAd63 ME-TRAP; error bars represent IQRs. G, Mean number of peptide pools recognized at different time points (data for all volunteers analyzed using 1-way analysis of variance with Bonferroni post test; error bars represent standard errors of the mean. H, Cultured ELISPOT responses compared with previous trials (data shown represents median and IQR, analyzed by Kruskal-Wallis test with Dunn post test. (*P < .05; x-axis displays regimes used in previous clinical trials D = DNA ME-TRAP, F = FP9 ME-TRAP, M = MVA ME-TRAP.)

Abbreviations: ChAd63, chimpanzee adenovirus; ELISPOT, enzyme-linked immunospot; i.d., intradermal; i.m., intramuscular; ME-TRAP, multiple epitope-thrombospondin–related adhesion protein; MVA, modified vaccinia virus Ankara; PBMCs, peripheral blood mononuclear cells; vp; viral particles.

Responses to ME-TRAP were detected 14 days after priming vaccination with ChAd63, with median ELISPOT responses per dose group ranging from 61–915 SFC/10⁶ PBMCs (hence SFC/M) with priming doses between 1 × 10⁸ and 2 × 10¹¹ vp (Figure 3B and 3D). Boosting with MVA ME-TRAP significantly augmented the immunogenicity with individual responses as high as 2465 SFC/M (medians ranging from 764 to 2063 SFC/M for 1 × 10⁸–2 × 10¹¹ vp) 7 days post-MVA ME-TRAP (Figure 3C and 3E). Response to the vaccine insert could be detected in all volunteers at their final visits, with excellent preservation of the effector immune response in the prime-boost volunteers, with medians of 246–1294 SFC/M across the different groups 3 months post boosting vaccination (Figure 3C).

Individual peak immune responses occurred either at 14 or 28 days post-ChAd63 ME-TRAP vaccination. Post priming vaccination, there was a trend toward higher responses at higher doses with a significant difference in ELISPOT response between 1 × 10⁸ and 2 × 10¹¹ vp ChAd63 ME-TRAP (Figure 3F; P = .005 Kruskal-Wallis test, medians ranging from 78.1–915 SFC/M). Post-MVA ME-TRAP immune responses were maximal at day 63 with a nonsignificant trend toward increasing responses as the priming dose increased.

To assess changes in the breadth of TRAP-specific T-cell responses by ELISPOT induced by both immunizations, the number of peptide pools (total of 6) in which responses per well were greater than a threshold of 100 SFC/M (after subtracting the background response) were summed for each individual, at every time point. Given the small number of samples for each dose group, data for all groups were pooled. A nonsignificant increase (Figure 3G) in the number of positive TRAP-specific peptide pools was observed following the first immunization (D14 mean, 1.0 [95% confidence interval {CI}, .4–1.6]), and this was significantly boosted by the second immunization (D63 mean, 3.0 [95% CI, 2.2–3.8] P < .001 compared with D14). This boosting effect of MVA ME-TRAP was maintained up to D140 (mean 1.4 [95% CI, .9–2.0] compared with D14, P < .05).

Cultured ELISPOT assay (cELISPOT) responses (Figure 3H) were present in 7 of 8 volunteers examined at day 140 but did not correlate significantly with peak ex vivo immune response (Pearson correlation r = −0.68, P = .2). Notably, cELISPOT responses in group 4, with a median cELISPOT response of 6638 SFC/10⁶ original PBMCs (interquartile range [IQR], 2901–9073) are double the highest value previously recorded with a regime of DNA and MVA ME-TRAP given multiple times, one of the most immunogenic and protective regimes we have previously trialed (median, 2900; IQR, 140–4160) [19].

TRAP-specific antibody responses were identified by enzyme-linked immunosorbent assay (ELISA) in all recipients of ChAd63, and were significantly boosted by MVA ME-TRAP (data not shown).

Flow Cytometry

T-cell phenotypes (ie, CD4⁺ vs CD8⁺) and functional capacities of vaccine-generated T-cell responses (ie, the production of cytokines IFN-γ, interleukin 2, and tumor necrosis factor α in response to a pool of all 57 peptides spanning the TRAP antigen were evaluated using flow cytometry. Assays were performed on cryopreserved PBMCs from volunteers in groups 2B (n = 2), 3B (n = 4), and 4B (n = 2) (Figure 4). No significant differences were observed between the different groups in terms of the percentage of cytokine secreting cells; thus, all data were pooled for further analysis.

View larger version:

� � � � � � In this page

� � � � � � In a new window

� � � � � � Download as PowerPoint Slide

Figure 4.

Flow cytometry. A, Percentage of parent populations (CD4⁺ or CD8⁺) secreting named cytokine over time. IFN-γ responses peak 7 days post-MVA boost with the frequency of CD8⁺ T cells secreting IFN-γ increasing significantly between baseline and D63 (P < .05, Kruskal-Wallis with Dunn posttest correction). B, Polyfunctionality of TRAP-specific CD4⁺ or CD8⁺ T cells over time. T cells capable of secreting all 3 cytokines are only detected after boosting with MVA.

Abbreviations: IFN, interferon; IL, interleukin; MVA, modified vaccinia virus Ankara; TNF, tumor necrosis factor; TRAP, thrombospondin-related adhesion protein.

Vaccination with ChAd63 ME-TRAP induced an increase in the percentage of antigen-specific CD4⁺ and CD8⁺ T cells capable of secreting cytokines of interest with responses boosted by MVA ME-TRAP. TRAP-specific CD8⁺ T cells secreting IFN-γ underwent an 8-fold increase between baseline (mean, 0.014% [95% CI, 0–.033%]) and day 63 (mean, 0.12% [95% CI: 0–.167%]), P < .05). Boosting also induced a marked expansion of polyfunctional T cells up to 140 days (Figure 4B).

Antivector Antibodies

Serum samples were examined for the presence of nAb to ChAd63 in 50 of 54 volunteers. Initially, volunteers with any evidence of nAb to ChAd63 were excluded for group 1; then approval was given to allow recruitment in groups 2–6 of subjects with nAb titer <1:200, and group 7 was subsequently approved for recruitment of volunteers with any nAb titer. Figure 5B shows the time course of nAb. In total, 35 of 50 (83%) subjects had no evidence of ChAd63 nAb at day 0, including 8 subjects receiving 1 × 10⁸ vp ChAd63 ME-TRAP (group 1), 4 of whom developed low levels after vaccination. Of the remaining subjects negative for nAb at day 0, >90% seroconverted after vaccination. ChAd63 dose correlated with peak nAb titer (Spearman rank correlation r = 0.54, P < .0001; n = 50), but no relationship was observed between baseline nAb and peak ELISPOT response (excluding volunteers from group 1 with no baseline nAb; r = 0.031, P = .85; Figure 5C, n = 42). In group 7, where any preexisting antibody titer was allowable, there was no evidence that higher baseline nAb titer reduced peak (r = 0.21, P = .71, n = 6) or day 140 ELISPOT response (r = −0.51, P = .30, n = 6).

View larger version:

� � � � � � In this page

� � � � � � In a new window

� � � � � � Download as PowerPoint Slide

Figure 5.

Antibodies. A, Median anti-ChAd63 antibody titers postvaccination. B, Correlation between day 0 anti-ChAd63 antibody titer and peak enzyme-linked immunospot result (r = 0.031, P = .85 by Spearman rank correlation [95% confidence interval, −.2843 to .3400]).

Abbreviation: ChAd63, chimpanzee adenovirus.

Reboosting

No serious vaccine-related adverse events were reported after either reboosting immunization. The reactogenicity profile of both vaccines was similar (Figure 6A).

Figure 6.

Reboosting. A, Local and systemic adverse events occurring post reboosting with ChAd63 ME-TRAP and MVA ME-TRAP. B, Interval between first boosting vaccination with MVA and reboosting with either vector. Bar represents median interval for each group. C, Median enzyme-linked immunospot (ELISPOT) responses after reboosting; peak response post-MVA reboost 1169 SFC/10⁶ peripheral blood mononuclear cells (PBMCs), peak response post-ChAd63 reboost 1558SFC/10⁶ PBMCs). D, Relationship between reboosting interval and response to reboost (Spearman rank correlation r = 0.64, P = .035). E, Cytokine responses to first and second boosting vaccinations for all subjects in group 8, showing percentage of parent population (either CD4⁺ or CD8⁺ T cells), secreting named cytokine.

Abbreviations: ChAd63, chimpanzee adenovirus; IFN, interferon; IL, interleukin; ME-TRAP, multiple epitope thrombospondin-related adhesion protein; MVA, modified vaccinia virus Ankara; TNF, tumor necrosis factor.

Stratification for time since last vaccination was effective, with a median of 236 days (IQR, 184.5–638) between last vaccination and reboost for the ChAd63 ME-TRAP recipients and 249 days (IQR, 172–606) for the MVA ME-TRAP recipients (Figure 6B and Supplementary figure 1B). ELISPOT responses were not significantly different prior to the reboosting immunization between those reboosted with ChAd63 and MVA (P = .66) and for both groups, the reboosting immunization resulted in a significant increase from pre-reboosting ELISPOT responses (median, 624 SFC/M; IQR, 294–839) prior to reboosting to a median of 1315 SFC/M [IQR, 1024–1991] at peak (P = .001; Figure 6C). There was no significant difference in the peak reboost responses induced by ChAd63 or MVA (1743 SFC/M [IQR, 994–2106] and 1280 SFC/M [IQR, 853–2060], respectively; P = .7). There was a correlation between reboosting interval and magnitude of the response to reboost by ELISPOT (Figure 6D).

Intracellular cytokine staining was performed on a subset of reboosted volunteers (n = 3 in each group) where cells were available. A comparable percentage of total antigen-specific CD8⁺ IFN-γ⁺ cells followed reboosting (ChAd63 median, 0.22% [range, 0–0.26%], MVA median, 0.410% [range, 0.009–0.142%], P = 1.0; Figure 6E).

Previous SectionNext Section

DISCUSSION

ChAd63 ME-TRAP at doses between 1 × 10⁸ and 2 × 10¹¹ vp has been used safely in this study and generates high levels of antigen-specific T cells which remain detectable for over 28 months post-MVA. Although other simian adenoviruses have shown promise in preclinical studies, this is the first report of the use of a nonhuman adenovirus as a vaccine vector in humans to our knowledge.

Vectored vaccines have shown considerable promise as vaccine candidates due to their ease of generation, often low-cost manufacture, and their ability to induce significant cellular immunity. However, to date their development has been limited by several obstacles. Some viral vectors, even within the adenovirus family, are much more potent than others, and only a limited number of serotypes show good immunogenicity. Second, for several vectors, proprietary cell lines are required for large-scale manufacture, and these are not widely available. Other vectors have been found to show significant genetic instability when produced at large scale. Usage of HEK293 cells, or the alternative PER.C6 cell line, facilitates easy growth of ChAd63, thus providing a manufacturing process that can be easily scaled up for mass production. Several thousand doses of vaccine were produced in our manufacturing runs in a process that is now very efficient. Finally, certain viral vectors are limited by high levels of preexisting immunity in many human populations, whereas ChAd63 has limited preexisting immunity in European and African populations.

In this trial, ChAd63 ME-TRAP has been shown to have a good safety profile despite relatively stringent adverse analysis (all adverse events occurring up to 28 days postvaccination deemed possibly, probably, or definitely related were analyzed). Rates and types of adverse events are comparable to ongoing trials using human adenovirus 5 as a vector. In a recent phase 1 trial of a human adenovirus 5 expressing glycoprotein (GP) from the Ebola virus species where 11 subjects received 2 × 10¹⁰ vp of vaccine, 6 moderate or severe systemic adverse events were reported at this dose (6 of 29 total systemic adverse events) [20]. In comparison, we report 1 moderate or severe systemic adverse event occurring post-ChAd63 ME-TRAP at 1 × 10¹⁰ vp (1 of 29 total systemic adverse events reported) making ChAd63 less reactogenic. Peiperl et al [21] assess safety and maximal tolerated dose of an adenoviral vaccine vector in volunteers without prior immunity, using a recombinant replication-defective adenovirus type 5 (rAd5) vaccine expressing HIV-1 Gag, Pol, and multiclade Env proteins. Here, 20 volunteers received 2 × 10¹¹ particle units of vaccine, and systemic adverse events were assessed for the 72 hours following vaccination. Fifteen volunteers report at least 1 moderate or severe systemic adverse event occurring postvaccination. In comparison, with ChAd63 ME-TRAP at the same dose, 10 volunteers were vaccinated and reported only 9 systemic adverse events postvaccination as moderate or severe.

MVA ME-TRAP is a well-characterized vaccine in terms of immunogenicity and once again is used safely in this trial. It has now been administered to >600 healthy volunteers in Oxford [22], The Gambia [23], and Kenya [24] without any serious adverse events with volunteers receiving between 1 and 3 intradermal doses of vaccine (3–50 × 10⁷ PFU per dose), at 3- to 4-week intervals.

The prime-boost vaccination regimen with ChAd63 and MVA ME-TRAP generated unprecedented levels of effector T-cell responses, as measured by ex vivo IFN-γ ELISPOT in comparison to previous malaria vaccine trials with the same antigenic insert. Responses here were both higher and different in quality. In contrast to average responses (at the peak time point) of approximately 450 SFC/M [18, 25], we now report average responses exceeding 2000 SFC/M. Second, by flow cytometry we observe that there are at least as many CD8⁺ as CD4⁺ gamma-interferon–secreting T cells induced at the peak time points, in contrast to previous prime-boost regimes using DNA and poxvirus-priming vectors, where predominantly CD4⁺ T-cell responses were induced. This ability to induce both high-level CD8⁺ and CD4⁺ responses with simian adenovirus–MVA prime-boost regimes should broaden the potential utility of this approach.

This simian adenovirus vector used alone without an MVA boost also compares very favorably in terms of immunogenicity with reports of HIV vaccine trials using the AdHu5 vector, although different inserts prevent a definitive comparison. Over 90% of our volunteers had detectable ELISPOT responses 4 weeks after the priming vaccination, and after 3 months, all subjects receiving adenovirus alone had a detectable immune response compared with recently reported HIV-1 vaccine trials using human adenovirus 5 expressing HIV gag (Ad5 gag), where after 3 doses of 1 × 10¹¹ vp Ad5 gag at week 8 only 53% of volunteers had a detectable response on ELISPOT [26].

Neutralizing antibodies to ChAd63 were induced in all volunteers. But titers did not correlate with the level of vaccine-induced immune response to the malaria insert, as measured by ELISPOT, nor with the frequency or grade of adverse events (data not shown). As discussed above, ChAd63 nAb are rare in the general population but are clearly detectable prior to vaccination in some individuals. It is unclear whether this is caused by cross-reactivity to ChAd63 of antibodies induced by a closely related human adenovirus, or by a low prevalence of ChAd63 infections in humans. In group 7 where individuals with any titer of ChAd63 nAb were enrolled, there was no reduction in the vaccine-induced immune response in those with preexisting antibodies to the vector. Moreover, volunteers could be safely reboosted with either MVA ME-TRAP or ChAd63 ME-TRAP at 5–30 months after their first MVA immunization with no impairment of vaccine immunogenicity, suggesting that these viral vectors are suitable for repeated usage with such an interval.

Previous SectionNext Section

CONCLUSION

This phase I clinical trial has shown that simian adenoviruses are safe when used alone or with an MVA boost with no evidence of dose limiting toxicity. Importantly, the cellular immunity induced to a full-length antigen by this vaccination strategy appears significantly greater than with any previously reported immunization regime.

Previous SectionNext Section

Supplementary Data

Supplementary materials are available at The Journal of Infectious Diseases online (http://www.oxfordjournals.org/our_journals/jid/). Supplementary materials consist of data provided by the author that are published to benefit the reader. The posted materials are not copyedited. The contents of all supplementary data are the sole responsibility of the authors. Questions or messages regarding errors should be addressed to the author.

�

• MAKING CIRCUMCISION EASIER 

MAKING CIRCUMCISION EASIER

From the New York Times, 30 January 2012

Best viewed at http://www.nytimes.com/2012/01/31/health/aids-prevention-inspires-ways-to-simplify-circumcision.html?tntemail1=y&emc=tnt&pagewanted=all

�

The day of the assembly-line circumcision is drawing closer.

Now that three studies have shown that circumcising adult heterosexual men is one of the most effective “vaccines” against AIDS — reducing the chances of infection by 60 percent or more — public health experts are struggling to find ways to make the process faster, cheaper and safer.

The goal is to circumcise 20 million African men by 2015, but only about 600,000 have had the operation thus far. Even a skilled surgeon takes about 15 minutes, most African countries are desperately short of surgeons, and there is no Mohels Without Borders.

So donors are pinning their hopes on several devices now being tested to speed things up.

Dr. Stefano Bertozzi, director of H.I.V. for the Bill and Melinda Gates Foundation, said it had its eyes on two, named PrePex and the Shang Ring, and was supporting efforts by the World Health Organization to evaluate them.

Circumcision is believe to protect heterosexual men because the foreskin has many Langerhans cells, which pick up viruses and “present” them to the immune system — which H.I.V. attacks.

PrePex, invented in 2009 by four Israelis after one of them, a urologist, heard an appeal for doctors to do circumcisions in Africa, was approved by the Food and Drug Administration three weeks ago. The W.H.O. will make a decision on it soon, said Mitchell Warren, an AIDS-prevention expert who closely follows the process.

From the initial safety studies done so far, PrePex is clearly faster, less painful and more bloodless than any of its current rivals. And it relies on the simplest and least-threatening technology — a rubber band.

The band compresses the foreskin against a plastic ring slipped inside it; the foreskin dies within hours for lack of blood and, after a week, falls off or can be clipped off “like a fingernail,” said Tzameret Fuerst, the company’s chief executive officer, who compared the process to the stump of an umbilical cord’s shriveling up and dropping off a few days after it is clamped.

It is done with topical anesthetic cream, and there is usually no bleeding. And PrePex can be put in place and removed by nurses with about three days’ training.

The rings come in five sizes, A through E, Ms. Fuerst said, “and you won’t believe how high-tech the rubber band is.” Each size must apply just enough pressure to cut off blood flow without being tight enough to cause pain.

The W.H.O., Mr. Warren said, is also evaluating the Shang Ring, a plastic two-ring clamp developed in China to treat conditions in which the foreskin becomes so tight that it cuts off urination.

However, it requires cutting off the excess foreskin beyond the clamp, which means the circumciser must inject anesthetics directly into the penis and groin, wait for them to take effect, create a sterile surgical field and be trained in minor surgery.

“The Shang is not as fast, but it’s faster than full-fledged surgery,” Mr. Warren said. “And it hasn’t submitted as much safety data.”

In a safety study presented at an AIDS conference last month, scientists from Rwanda’s health ministry said they had used PrePex to circumcise 590 men. Only two had “moderate” complications; one was fixed with a single suture, and one required a new band in a different spot.

According to Dr. Jason Reed, an epidemiologist in the global AIDS division of the Centers for Disease Control and Prevention, 2 of 590, or 0.34 percent, is a tenth the typical complication rate of surgical circumcision.

None of the men became infected.

On the 10-point pain scale, they reported on average only about 1 when the ring was placed and only 3 when it was removed (about the same level of pain caused by erections during the week they wore it).

By the end of the study, the two-nurse teams could do a procedure in three minutes.

By contrast, Dr. Reed said, the best surgical “assembly lines” — a practice being pioneered in Africa with American taxpayer support — can get down to seven minutes per patient, but only by getting six nurses and a surgeon into a tight harmony.

In theory, he said, breaking that into three two-nurse PrePex teams could mean circumcising around 400 men a day, rather than the 60 to 80 a busy team now does. And the surgeon could go do something more important.

In fact, Dr. Reed said, American AIDS dollars for circumcisions often go toward an operating room with lights and an instrument sterilizer. Instead of circumcisions, hospitals are more likely to use it for procedures like saving women in obstructed labor.

“Which is understandable — of course that takes precedence,” he said. “But then the circumcisions don’t get done.”

Robert C. Bailey, an epidemiologist at the University of Illinois at Chicago who helped design Kenya’s circumcision efforts, opposes timesaving devices because training nurses in minor surgery has other benefits, he said. A trained nurse could close a wound or take out an appendix, for example. And the time-consuming parts of the process are counseling and H.I.V. testing, Dr. Bailey said, so “doing it in five minutes instead of 20 is trivial.”

But he conceded, “If PrePex really doesn’t require anesthesia, that’s truly an advance.”

Rwanda is training 150 two-nurse teams; it is a small country, but it serves as a bellwether for Africa because its health care system is well organized, government corruption scandals are rare, and it is heavily supported by donor funds.

Other, rival devices are not far along in safety testing or are failing it.

The Tara KLamp, manufactured in Malaysia since the 1990s, has created controversy in South Africa. It is a hinged plastic bracket the size of a small drinking cup. A plastic tube goes over the head of the penis, and the foreskin is pulled up it and painfully crushed by the bracket. Then the whole contraption must be worn at least five days. A 2005 clinical trial in South Africa was stopped early after the device caused far more injuries and infections than surgery did.

The national health ministry has banned it in most of South Africa, but it is still used heavily in KwaZulu-Natal Province, which has the country’s highest AIDS rate and where the Zulu king, Goodwill Zwelithini, reversing 200 years of tradition, ordered that all Zulu men circumcised.

The W.H.O. knows about the stopped trial and is not considering the KLamp, Mr. Warren said.

Dr. Reed said he had heard that another device, Ali’s Klamp, was being tested in Kenya under protocols that seemed to match W.H.O. requirements. According to Circlist.com, a circumcision information Web site, it is a Turkish device dating to 2007, and works on principles similar to those of the Tara KLamp and another device, the SmartKlamp, approved by the F.D.A. in 2004.

PrePex was cleared by the F.D.A. because it was judged “substantially equivalent” to the SmartKlamp, Ms. Fuerst said. Proving equivalence in safety to an approved device is the fastest way to get approval, she said, although the technology is quite different.

PrePex’s ultimate cost is still being negotiated with donor agencies and foundations, Ms. Fuerst said, but may end up in the $15-to-$20 range, about the same as a surgical circumcision kit.

This article has been revised to reflect the following correction:

Correction: January 30, 2012

An earlier version of this article misstated the number of inventors of the PrePex device. There were four, not three.

A version of this article appeared in print on January 31, 2012, on page D1 of the New York edition with the headline: AIDS Prevention Inspires Ways To Make Circumcisions Easier.

�