Tuesday, 31st of January 2012 |
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. �
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
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
+ Author Affiliations
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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.
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.
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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.
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).
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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.
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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.
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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).
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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).
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.
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.
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.
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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
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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.
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