Comment
suspected meningitis seems to be low in US emergency departments, despite recommendations.13 These findings suggest that the reported change in mortality is more probably related to other factors, including improved detection of pretreated cases, concurrent implementation of sepsis care bundles, and the decreasing prevalence of the vaccine serotypes with the highest case-fatality rates.14 Ecological studies of routinely collected data have an important role in programme assessment. Those studies using administrative databases are inexpensive and can capture long-term trends if their limitations are recognised and their findings correlated with laboratory surveillance.4 High quality laboratory surveillance is more costly but is essential to quantify serotypespecific effects, such as with meningococcal C disease.6 Background fluctuations in baseline incidence will make the assessment of any vaccine programmes for group B meningococcus outside outbreak settings challenging, precipitating a need for more rigorous studies to confirm effectiveness. Although such studies are difficult to do and expensive, the cost of failing to do them includes lost opportunities if better strategies are consequently foregone or remain untested. *Thomas L Snelling, Peter B McIntyre Telethon Kids Institute, The University of Western Australia, Subiaco, WA 6007, Australia (TLS); Menzies School of Health Research and Charles Darwin University, Tiwi, NT, Australia (TLS); and National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases (PBM), and Discipline of Paediatrics and Child Health (PBM), The Children’s Hospital at Westmead, Westmead, NSW, Australia [email protected]
We declare no competing interests. 1 2 3
4
5
6
7
8
9 10
11
12 13 14
McIntyre PB, O’Brien KL, Greenwood B, van de Beek D. Effect of vaccines on bacterial meningitis worldwide. Lancet 2012; 380: 1703–11. van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of bacterial meningitis. Lancet 2012; 380: 1693–702. Gedeborg R, Furebring M, Michaelsson K. Diagnosis-dependent misclassification of infections using administrative data variably affected incidence and mortality estimates in ICU patients. J Clin Epidemiol 2007; 60: 155–62. Martin NG, Sadarangani M, Pollard AJ, Goldacre MJ. Hospital admission rates for meningitis and septicaemia caused by Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae in children in England over five decades: a population-based observational study. Lancet Infect Dis 2014; 14: 397–405. Castelblanco RL, Lee M, Hasbun R. Epidemiology of bacterial meningitis in the USA from 1997 to 2010: a population observation-based study. Lancet Infect Dis 2014; published online Aug 5. http://dx.doi.org/10.1016/S14733099(14)70805-9. Bijlsma MW, Bekker V, Brouwer MC, Spanjaard L, van de Beek D, van der Ende A. Epidemiology of invasive meningococcal disease in the Netherlands, 1960–2012: an analysis of national surveillance data. Lancet Infect Dis 2014; published online Aug 5. http://dx.doi.org/10.1016/ S1473-3099(14)70806-0. Feikin DR, Kagucia EW, Loo JD, et al. Serotype-specific changes in invasive pneumococcal disease after pneumococcal conjugate vaccine introduction: a pooled analysis of multiple surveillance sites. PLoS Med 2013; 10: e1001517. Miller E, Andrews NJ, Waight PA, Slack MP, George RC. Herd immunity and serotype replacement 4 years after seven-valent pneumococcal conjugate vaccination in England and Wales: an observational cohort study. Lancet Infect Dis 2011; 11: 760–68. Jafri RZ, Ali A, Messonnier NE, et al. Global epidemiology of invasive meningococcal disease. Popul Health Metr 2013; 11: 17. Cohn AC, MacNeil JR, Harrison LH, et al. Changes in Neisseria meningitidis disease epidemiology in the United States, 1998–2007: implications for prevention of meningococcal disease. Clin Infect Dis 2010; 50: 184–91. Cabana MD, Rand CS, Powe NR, et al. Why don’t physicians follow clinical practice guidelines? A framework for improvement. JAMA 1999; 282: 1458– 65. Brouwer MC, McIntyre P, Prasad K, van de Beek D. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev 2013; 6: CD004405. Takhar SS, Ting SA, Camargo CA Jr, Pallin DJ. U.S. emergency department visits for meningitis, 1993-2008. Acad Emerg Med 2012; 19: 632–39. Thigpen MC, Whitney CG, Messonnier NE, et al. Bacterial meningitis in the United States, 1998-2007. N Engl J Med 2011; 364: 2016–25.
Moving HIV PrEP from research into practice Pre-exposure prophylaxis (PrEP) for HIV has been studied in five large and rigorous randomised controlled trials, three of which showed efficacy,1–5 but several questions remain. Is PrEP a useful public health intervention? Will those most at-risk use it? Will they adhere to it? What is its real-world safety profile? And will it reduce or increase high-risk sexual behaviour and HIV incidence? In The Lancet Infectious Diseases, Robert Grant and colleagues6 report the results of iPrEx Open-Label Extension, the first open-label study of PrEP. They www.thelancet.com/infection Vol 14 September 2014
enrolled 1603 HIV-negative men and transgender women who have sex with men who previously were participants of three randomised double-blind PrEP studies (iPrEx, ATN 082, and US Safety Study).7,8 Followup lasted 72 weeks after enrolment. Uptake of PrEP was high: 76% of participants opted to take PrEP at some point during follow-up. Those reporting condomless receptive anal intercourse and those who were herpes simplex virus 2 seropositive were more likely to start PrEP. Incidence among participants who did not use PrEP was 2·6 infections per
Published Online July 22, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70747-9 See Articles page 820
781
Comment
Kimberly White/Reuters/Corbis
100 person-years versus 1·8 infections per 100 personyears for those who did use PrEP, with the difference being non-significant but perhaps clinically important: HIV incidence in the placebo group of the randomised iPrEX study was 3·9 infections per 100 person-years. Adherence (as measured by drug concentrations in dried blood spots) was better among older participants, those with more education, and those who engaged in riskier sexual behaviours (according to several measures). No incident HIV infections occurred in participants with drug concentrations commensurate with taking four to seven tablets per week. Side-effects were few. Reports of condomless receptive anal intercourse fell over the course of the study—for both on-PrEP and off-PrEP participants. The most common pattern of use of PrEP was initial uptake with subsequent fall-off. Is PrEP uptake by 76% of participants enough? Because the participants were in a previous trial, the sample is biased towards a highly motivated population; therefore one might have expected nearly universal uptake. Toxic effects do not seem to be limiting uptake: “participant preference” was the most common reason for drug interruption. Are daily-dosing fatigue or the stigma of using a drug that has been saddled with an association with promiscuity contributing to attenuated adherence despite persistent or increased risk? Optimisation of prevention combinations is crucial to overall success of efforts to eliminate HIV. The overall HIV incidence for those receiving PrEP in the open-label extension was 1·8 infections per 100 person-years, compared with the 2·2 per 100 person-years for those assigned to active tenofovir and emtricitabine in the parent-blinded iPrEX study. Why are incidences with open-label treatment not vanishingly low? iPrEX wisely combined drug prophylaxis with other HIV prevention services, but it seems that even this approach is insufficient. The open-label extension study shows that four or more doses (on average), as assessed by dried blood spots, provided nearly complete protection against HIV acquisition. But how does the timing of missed doses— and particularly multiple missed doses—attenuate efficacy? It is inadvisable to interpret these findings in a way that encourages less-than-daily dosing at present. Decreases in condomless receptive anal intercourse, reported in both on-PrEP and off-PrEP groups, supports the potency of the study’s prevention package and 782
suggests an absence of much-feared risk compensation in an open-label study. It will be particularly important to see whether this finding holds true beyond clinical trial settings. The incidence of syphilis was much the same in on-PrEP and off-PrEP participants, although we do not have a full dataset for all incident sexually transmitted infections to fully interpret these findings. Finally, only one case of treatment-emergent viral resistance (Met184Val) was reported. The study allowed at maximum intervals of 12 weeks between visits for HIV testing; therefore patients infected soon after a visit could spend almost 3 months taking non-suppressive tenofovir and emtricitabine, increasing the selection pressure for resistant viral species. How often resistance to emtricitabine develops, and whether seroconversion with tenofovir-resistant virus occurs will be important to see in clinical practice. WHO and the US Centers for Disease Control and Prevention recommend the broad use of daily oral PrEP for HIV prevention in at-risk populations,9,10 acknowledging the urgent need for new prevention strategies, and the need to provide clinicians with concrete guidance on the use of a complex and nuanced intervention. Although the study of Grant and colleagues advances our understanding of oral PrEP, and informs the thresholds of protection, it raises nearly as many questions as it answers. We eagerly await the upcoming results from a cadre of open-label studies in which tenofovir and emtricitabine is being provided to people who have not previously participated in pivotal randomised studies. Because choice between prevention options remains paramount to successful HIV prevention, we also look forward to the development of new drugs and preparations for PrEP, including topical gels, injectable antiviral drugs, and immunotherapies. The future is rich with possibility, but we have far to go to realise the full potential of PrEP. Raphael J Landovitz, Thomas J Coates UCLA Center for Clinical AIDS Research and Education (RJL), UCLA Center for World Health (TJC), Division of Infectious Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 90049, USA [email protected] RJL has been supplied drugs from Gilead Sciences for research studies of pre-exposure prophylaxis. TJC declares no competing interests. 1
Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010; 363: 2587–99.
www.thelancet.com/infection Vol 14 September 2014
Comment
2
3
4 5
6
Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012; 367: 399–410. Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med 2012; 367: 423–34. Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med 2012; 367: 411–22. Marrazzo JM, Ramjee G, Nair G, et al. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofoviremtricitabine, or vaginal tenofovir gel in the VOICE Study (MTN 003). 20th Conference on Retroviruses and Opportunistic Infections, 2013; Atlanta, GA, USA. Abstract 26LB. Grant RM, Anderson PL, McMahan V, et al for the iPrEx study team. Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study. Lancet Infect Dis 2014; published online July 22. http://dx.doi.org/10.1016/ S1473-3099(14)70847-3.
7
8
9
10
Hosek SG, Siberry G, Bell M, et al. The acceptability and feasibility of an HIV preexposure prophylaxis (PrEP) trial with young men who have sex with men. J Acquir Immune Defic Syndr 2013; 62: 447–56. Grohskopf LA, Chillag KL, Gvetadze R, et al. Randomized trial of clinical safety of daily oral tenofovir disoproxil fumarate among HIV-uninfected men who have sex with men in the United States. J Acquir Immune Defic Syndr 2013; 64: 79–86. US Public Health Service. Preexposure prophylaxis for the prevention of HIV infection in the United States - 2014 - a clinical practice guideline. http://www.cdc.gov/hiv/prevention/research/prep/ (accessed July 12, 2014). WHO. Consolidated guidelines on HIV prevention, diagnosis, treatment, and care for key populations. http://www.who.int/hiv/pub/guidelines/ keypopulations/en/ (accessed July 12, 2014).
The mosquito-borne dengue virus is a great concern to human health worldwide, leading to 93 million cases per year, many serious.1 This status is exacerbated by the absence of a vaccine. Despite many attempts to develop vaccines, success has been elusive; large-scale trials with attenuated yellow fever–dengue virus chimeric vaccines to stimulate broad immunity against the four dengue virus serotypes have produced largely disappointing results.2 In The Lancet Infectious Diseases, Jorge Osorio and colleagues have done a randomised, placebo-controlled, phase 1 study3 of the safety and immunogenicity of a live attenuated dengue serotype-2 strain (DENVax-2), also expressing structural genes for serotypes 1, 3, and 4, to produce a tetravalent dengue vaccine representing each of the four serotypes, with the goal of stimulating broadbased protective immunity. 96 flavivirus-naive, healthy adults in Rionegro, Columbia—a town located 2142 m above sea level, far from dengue virus and its transmitting vector, Aedes aegypti—received either high-dose or lowdose vaccine formulations. The vaccine was well tolerated in study participants who received two high or two low doses intradermally or subcutaneously. 73 (96%) of 76 participants seroconverted to three of the four serotypes, and 47 (62%) had antibody responses to all four serotypes after the second dose. Infectious DenVAX viruses were detected in ten (25%) of 40 participants in the lowdose group and 13 (33%) of 39 participants in the high-dose group. Although encouraging, the spectre hovering above these results is antibody-dependent enhancement of dengue virus in individuals exposed to natural infection, www.thelancet.com/infection Vol 14 September 2014
and its association with dengue shock syndrome and dengue haemorrhagic fever. Antibody-dependent enhancement is noted at subneutralising titres of antiviral antibody, so ideally, vaccines should drive strong, specific antibody responses to natural virus challenge and should sustain such responses to clear the infecting virus; this scenario becomes a crucial balancing act. Antibody-dependent enhancement was first reported in vitro by Hawkes and Lafferty4 and an explanation for plaque enhancement was proposed later by Kliks and Halstead.5 Early data suggested that antibody-dependent enhancement happens in vivo, with the finding of enhanced viraemia in monkeys who had received a second infection with dengue serotype 2.6 Underpinning antibody-dependent enhancement in monocyte and macrophage cells, in addition to enhanced virus uptake, is the suppression of early inflammatory responses via disruption of specific transcription factor activity.7 How the disruption of early inflammatory gene expression affects eventual adaptive immune responses should be of interest to vaccine developers. Another imperative for developers of dengue vaccines is to understand the physiological context of virus enhancement by antibody-dependent enhancement, dysregulation of early immune response, and the desired outcome of side-effect-free broad-based protection. 25 years ago, antibody-dependent enhancement in monocytes was identified as a risk factor for dengue shock syndrome and dengue haemorrhagic fever in Thai children,8 whereas later studies showed no correlation of antibody-dependent enhancement with disease symptoms and viraemia.9 Careful studies by Vaughn and
London School Of Hygiene And Tropical Medicine/SPL
Dengue virus and host antibody: a dangerous balancing act
Published Online July 24, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70843-6 See Articles page 830
783
suspected meningitis seems to be low in US emergency departments, despite recommendations.13 These findings suggest that the reported change in mortality is more probably related to other factors, including improved detection of pretreated cases, concurrent implementation of sepsis care bundles, and the decreasing prevalence of the vaccine serotypes with the highest case-fatality rates.14 Ecological studies of routinely collected data have an important role in programme assessment. Those studies using administrative databases are inexpensive and can capture long-term trends if their limitations are recognised and their findings correlated with laboratory surveillance.4 High quality laboratory surveillance is more costly but is essential to quantify serotypespecific effects, such as with meningococcal C disease.6 Background fluctuations in baseline incidence will make the assessment of any vaccine programmes for group B meningococcus outside outbreak settings challenging, precipitating a need for more rigorous studies to confirm effectiveness. Although such studies are difficult to do and expensive, the cost of failing to do them includes lost opportunities if better strategies are consequently foregone or remain untested. *Thomas L Snelling, Peter B McIntyre Telethon Kids Institute, The University of Western Australia, Subiaco, WA 6007, Australia (TLS); Menzies School of Health Research and Charles Darwin University, Tiwi, NT, Australia (TLS); and National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases (PBM), and Discipline of Paediatrics and Child Health (PBM), The Children’s Hospital at Westmead, Westmead, NSW, Australia [email protected]
We declare no competing interests. 1 2 3
4
5
6
7
8
9 10
11
12 13 14
McIntyre PB, O’Brien KL, Greenwood B, van de Beek D. Effect of vaccines on bacterial meningitis worldwide. Lancet 2012; 380: 1703–11. van de Beek D, Brouwer MC, Thwaites GE, Tunkel AR. Advances in treatment of bacterial meningitis. Lancet 2012; 380: 1693–702. Gedeborg R, Furebring M, Michaelsson K. Diagnosis-dependent misclassification of infections using administrative data variably affected incidence and mortality estimates in ICU patients. J Clin Epidemiol 2007; 60: 155–62. Martin NG, Sadarangani M, Pollard AJ, Goldacre MJ. Hospital admission rates for meningitis and septicaemia caused by Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae in children in England over five decades: a population-based observational study. Lancet Infect Dis 2014; 14: 397–405. Castelblanco RL, Lee M, Hasbun R. Epidemiology of bacterial meningitis in the USA from 1997 to 2010: a population observation-based study. Lancet Infect Dis 2014; published online Aug 5. http://dx.doi.org/10.1016/S14733099(14)70805-9. Bijlsma MW, Bekker V, Brouwer MC, Spanjaard L, van de Beek D, van der Ende A. Epidemiology of invasive meningococcal disease in the Netherlands, 1960–2012: an analysis of national surveillance data. Lancet Infect Dis 2014; published online Aug 5. http://dx.doi.org/10.1016/ S1473-3099(14)70806-0. Feikin DR, Kagucia EW, Loo JD, et al. Serotype-specific changes in invasive pneumococcal disease after pneumococcal conjugate vaccine introduction: a pooled analysis of multiple surveillance sites. PLoS Med 2013; 10: e1001517. Miller E, Andrews NJ, Waight PA, Slack MP, George RC. Herd immunity and serotype replacement 4 years after seven-valent pneumococcal conjugate vaccination in England and Wales: an observational cohort study. Lancet Infect Dis 2011; 11: 760–68. Jafri RZ, Ali A, Messonnier NE, et al. Global epidemiology of invasive meningococcal disease. Popul Health Metr 2013; 11: 17. Cohn AC, MacNeil JR, Harrison LH, et al. Changes in Neisseria meningitidis disease epidemiology in the United States, 1998–2007: implications for prevention of meningococcal disease. Clin Infect Dis 2010; 50: 184–91. Cabana MD, Rand CS, Powe NR, et al. Why don’t physicians follow clinical practice guidelines? A framework for improvement. JAMA 1999; 282: 1458– 65. Brouwer MC, McIntyre P, Prasad K, van de Beek D. Corticosteroids for acute bacterial meningitis. Cochrane Database Syst Rev 2013; 6: CD004405. Takhar SS, Ting SA, Camargo CA Jr, Pallin DJ. U.S. emergency department visits for meningitis, 1993-2008. Acad Emerg Med 2012; 19: 632–39. Thigpen MC, Whitney CG, Messonnier NE, et al. Bacterial meningitis in the United States, 1998-2007. N Engl J Med 2011; 364: 2016–25.
Moving HIV PrEP from research into practice Pre-exposure prophylaxis (PrEP) for HIV has been studied in five large and rigorous randomised controlled trials, three of which showed efficacy,1–5 but several questions remain. Is PrEP a useful public health intervention? Will those most at-risk use it? Will they adhere to it? What is its real-world safety profile? And will it reduce or increase high-risk sexual behaviour and HIV incidence? In The Lancet Infectious Diseases, Robert Grant and colleagues6 report the results of iPrEx Open-Label Extension, the first open-label study of PrEP. They www.thelancet.com/infection Vol 14 September 2014
enrolled 1603 HIV-negative men and transgender women who have sex with men who previously were participants of three randomised double-blind PrEP studies (iPrEx, ATN 082, and US Safety Study).7,8 Followup lasted 72 weeks after enrolment. Uptake of PrEP was high: 76% of participants opted to take PrEP at some point during follow-up. Those reporting condomless receptive anal intercourse and those who were herpes simplex virus 2 seropositive were more likely to start PrEP. Incidence among participants who did not use PrEP was 2·6 infections per
Published Online July 22, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70747-9 See Articles page 820
781
Comment
Kimberly White/Reuters/Corbis
100 person-years versus 1·8 infections per 100 personyears for those who did use PrEP, with the difference being non-significant but perhaps clinically important: HIV incidence in the placebo group of the randomised iPrEX study was 3·9 infections per 100 person-years. Adherence (as measured by drug concentrations in dried blood spots) was better among older participants, those with more education, and those who engaged in riskier sexual behaviours (according to several measures). No incident HIV infections occurred in participants with drug concentrations commensurate with taking four to seven tablets per week. Side-effects were few. Reports of condomless receptive anal intercourse fell over the course of the study—for both on-PrEP and off-PrEP participants. The most common pattern of use of PrEP was initial uptake with subsequent fall-off. Is PrEP uptake by 76% of participants enough? Because the participants were in a previous trial, the sample is biased towards a highly motivated population; therefore one might have expected nearly universal uptake. Toxic effects do not seem to be limiting uptake: “participant preference” was the most common reason for drug interruption. Are daily-dosing fatigue or the stigma of using a drug that has been saddled with an association with promiscuity contributing to attenuated adherence despite persistent or increased risk? Optimisation of prevention combinations is crucial to overall success of efforts to eliminate HIV. The overall HIV incidence for those receiving PrEP in the open-label extension was 1·8 infections per 100 person-years, compared with the 2·2 per 100 person-years for those assigned to active tenofovir and emtricitabine in the parent-blinded iPrEX study. Why are incidences with open-label treatment not vanishingly low? iPrEX wisely combined drug prophylaxis with other HIV prevention services, but it seems that even this approach is insufficient. The open-label extension study shows that four or more doses (on average), as assessed by dried blood spots, provided nearly complete protection against HIV acquisition. But how does the timing of missed doses— and particularly multiple missed doses—attenuate efficacy? It is inadvisable to interpret these findings in a way that encourages less-than-daily dosing at present. Decreases in condomless receptive anal intercourse, reported in both on-PrEP and off-PrEP groups, supports the potency of the study’s prevention package and 782
suggests an absence of much-feared risk compensation in an open-label study. It will be particularly important to see whether this finding holds true beyond clinical trial settings. The incidence of syphilis was much the same in on-PrEP and off-PrEP participants, although we do not have a full dataset for all incident sexually transmitted infections to fully interpret these findings. Finally, only one case of treatment-emergent viral resistance (Met184Val) was reported. The study allowed at maximum intervals of 12 weeks between visits for HIV testing; therefore patients infected soon after a visit could spend almost 3 months taking non-suppressive tenofovir and emtricitabine, increasing the selection pressure for resistant viral species. How often resistance to emtricitabine develops, and whether seroconversion with tenofovir-resistant virus occurs will be important to see in clinical practice. WHO and the US Centers for Disease Control and Prevention recommend the broad use of daily oral PrEP for HIV prevention in at-risk populations,9,10 acknowledging the urgent need for new prevention strategies, and the need to provide clinicians with concrete guidance on the use of a complex and nuanced intervention. Although the study of Grant and colleagues advances our understanding of oral PrEP, and informs the thresholds of protection, it raises nearly as many questions as it answers. We eagerly await the upcoming results from a cadre of open-label studies in which tenofovir and emtricitabine is being provided to people who have not previously participated in pivotal randomised studies. Because choice between prevention options remains paramount to successful HIV prevention, we also look forward to the development of new drugs and preparations for PrEP, including topical gels, injectable antiviral drugs, and immunotherapies. The future is rich with possibility, but we have far to go to realise the full potential of PrEP. Raphael J Landovitz, Thomas J Coates UCLA Center for Clinical AIDS Research and Education (RJL), UCLA Center for World Health (TJC), Division of Infectious Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 90049, USA [email protected] RJL has been supplied drugs from Gilead Sciences for research studies of pre-exposure prophylaxis. TJC declares no competing interests. 1
Grant RM, Lama JR, Anderson PL, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med 2010; 363: 2587–99.
www.thelancet.com/infection Vol 14 September 2014
Comment
2
3
4 5
6
Baeten JM, Donnell D, Ndase P, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med 2012; 367: 399–410. Thigpen MC, Kebaabetswe PM, Paxton LA, et al. Antiretroviral preexposure prophylaxis for heterosexual HIV transmission in Botswana. N Engl J Med 2012; 367: 423–34. Van Damme L, Corneli A, Ahmed K, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med 2012; 367: 411–22. Marrazzo JM, Ramjee G, Nair G, et al. Pre-exposure prophylaxis for HIV in women: daily oral tenofovir, oral tenofoviremtricitabine, or vaginal tenofovir gel in the VOICE Study (MTN 003). 20th Conference on Retroviruses and Opportunistic Infections, 2013; Atlanta, GA, USA. Abstract 26LB. Grant RM, Anderson PL, McMahan V, et al for the iPrEx study team. Uptake of pre-exposure prophylaxis, sexual practices, and HIV incidence in men and transgender women who have sex with men: a cohort study. Lancet Infect Dis 2014; published online July 22. http://dx.doi.org/10.1016/ S1473-3099(14)70847-3.
7
8
9
10
Hosek SG, Siberry G, Bell M, et al. The acceptability and feasibility of an HIV preexposure prophylaxis (PrEP) trial with young men who have sex with men. J Acquir Immune Defic Syndr 2013; 62: 447–56. Grohskopf LA, Chillag KL, Gvetadze R, et al. Randomized trial of clinical safety of daily oral tenofovir disoproxil fumarate among HIV-uninfected men who have sex with men in the United States. J Acquir Immune Defic Syndr 2013; 64: 79–86. US Public Health Service. Preexposure prophylaxis for the prevention of HIV infection in the United States - 2014 - a clinical practice guideline. http://www.cdc.gov/hiv/prevention/research/prep/ (accessed July 12, 2014). WHO. Consolidated guidelines on HIV prevention, diagnosis, treatment, and care for key populations. http://www.who.int/hiv/pub/guidelines/ keypopulations/en/ (accessed July 12, 2014).
The mosquito-borne dengue virus is a great concern to human health worldwide, leading to 93 million cases per year, many serious.1 This status is exacerbated by the absence of a vaccine. Despite many attempts to develop vaccines, success has been elusive; large-scale trials with attenuated yellow fever–dengue virus chimeric vaccines to stimulate broad immunity against the four dengue virus serotypes have produced largely disappointing results.2 In The Lancet Infectious Diseases, Jorge Osorio and colleagues have done a randomised, placebo-controlled, phase 1 study3 of the safety and immunogenicity of a live attenuated dengue serotype-2 strain (DENVax-2), also expressing structural genes for serotypes 1, 3, and 4, to produce a tetravalent dengue vaccine representing each of the four serotypes, with the goal of stimulating broadbased protective immunity. 96 flavivirus-naive, healthy adults in Rionegro, Columbia—a town located 2142 m above sea level, far from dengue virus and its transmitting vector, Aedes aegypti—received either high-dose or lowdose vaccine formulations. The vaccine was well tolerated in study participants who received two high or two low doses intradermally or subcutaneously. 73 (96%) of 76 participants seroconverted to three of the four serotypes, and 47 (62%) had antibody responses to all four serotypes after the second dose. Infectious DenVAX viruses were detected in ten (25%) of 40 participants in the lowdose group and 13 (33%) of 39 participants in the high-dose group. Although encouraging, the spectre hovering above these results is antibody-dependent enhancement of dengue virus in individuals exposed to natural infection, www.thelancet.com/infection Vol 14 September 2014
and its association with dengue shock syndrome and dengue haemorrhagic fever. Antibody-dependent enhancement is noted at subneutralising titres of antiviral antibody, so ideally, vaccines should drive strong, specific antibody responses to natural virus challenge and should sustain such responses to clear the infecting virus; this scenario becomes a crucial balancing act. Antibody-dependent enhancement was first reported in vitro by Hawkes and Lafferty4 and an explanation for plaque enhancement was proposed later by Kliks and Halstead.5 Early data suggested that antibody-dependent enhancement happens in vivo, with the finding of enhanced viraemia in monkeys who had received a second infection with dengue serotype 2.6 Underpinning antibody-dependent enhancement in monocyte and macrophage cells, in addition to enhanced virus uptake, is the suppression of early inflammatory responses via disruption of specific transcription factor activity.7 How the disruption of early inflammatory gene expression affects eventual adaptive immune responses should be of interest to vaccine developers. Another imperative for developers of dengue vaccines is to understand the physiological context of virus enhancement by antibody-dependent enhancement, dysregulation of early immune response, and the desired outcome of side-effect-free broad-based protection. 25 years ago, antibody-dependent enhancement in monocytes was identified as a risk factor for dengue shock syndrome and dengue haemorrhagic fever in Thai children,8 whereas later studies showed no correlation of antibody-dependent enhancement with disease symptoms and viraemia.9 Careful studies by Vaughn and
London School Of Hygiene And Tropical Medicine/SPL
Dengue virus and host antibody: a dangerous balancing act
Published Online July 24, 2014 http://dx.doi.org/10.1016/ S1473-3099(14)70843-6 See Articles page 830
783
