The Weekly NewsDigest is a compilation of HIV prevention research media coverage and relevant science in peer-reviewed journals; material on
other reproductive health issues; and matters of policy and politics relevant to HIV prevention research, development and advocacy.
Its purpose is to raise awareness around the range of opinions and information about HIV prevention research disseminated in the press and
scientific journals and provide a neutral, objective basis for decision-making and evidence-based advocacy.
When Secretary of State Hilary Clinton made a historic speech in Geneva on Dec. 8 calling for recognition of gay rights and support for those who brave hostility to defend gay rights, she might have been speaking of the Rev. MacDonald Semberka who was in the audience listening. On the evening of Sept. 11, 2011, Sembereka, a Malawian Episcopalian, found his house reduced to unrecognizable rubble by a petrol bomb. A month later, he borrowed money for airfare so he could attend a conference at Union Theological Seminary, a Manhattan institution with a long history of social activism... Sembereka is one of a small but growing group of African religious leaders who have taken great personal and professional hits for supporting LGBT rights. For their efforts, they have faced violence, professional alienation and social ostricization. Yet these straight men and women, primarily Christian clergy, continue to criticize the intensifying vitriol and violence against gay Africans.
For the most part, African faith leaders have either fanned the flames of homophobia or stayed quiet on the issue. In some cases, they have been the key agitators of anti-gay attitudes in their countries... Where religion plays a significant role in the lives of many Africans, faith leaders yield great influence over politics and in setting the moral compass of most African societies. Last spring when Kenyan President Mwai Kibaki nominated Willy Mutunga, a pro-gay judge, many of the country's religious leaders sprang into action to oppose his nomination. Making matters worse for them, Nancy Baraza, the president's choice for the deputy chief justice, was also supportive of gay rights. For two months, substantive issues were sidelined for questions on the nominees' sexuality. The two nominees, both straight, were eventually confirmed as chief and deputy chief justice. Activists in Kenya and across Africa hailed this as an unparalleled victory in their struggle for equality... Methodist Rev. John Makokah of Kenya, who's been blasted for his pro-gay views, said, "We have a long way to go but Willy Mutunga and Nancy Baraza will help usher a new dawn for persecuted homosexuals." But the hearings in the Kenyan parliament last summer also demonstrated the strong sway of religion on government decisions.
Say "placebo effect" and most people think of the boost they may get from a sugar pill simply because they believe it will work. But more and more research suggests there is more than a fleeting boost to be gained from placebos. A particular mind-set or belief about one's body or health may lead to improvements in disease symptoms as well as changes in appetite, brain chemicals and even vision, several recent studies have found, highlighting how fundamentally the mind and body are connected. It doesn't seem to matter whether people know they are getting a placebo and not a "real" treatment... Researchers want to know more about how the placebo effect works, and how to increase and decrease it...
Ted Kaptchuk, director of Harvard's Program in Placebo Studies and the Therapeutic Encounter, and colleagues demonstrated that deception isn't necessary for the placebo effect to work... Why did the placebo work--even after patients were told they weren't getting real medicine? Expectations play a role, Dr. Kaptchuk says. Even more likely is that patients were conditioned to a positive environment, and the innovative approach and daily ritual of taking the pill created an openness to change, he says. Do placebos work on the actual condition, or on patients' perception of their symptoms?... "Right now, I think evidence is that placebo changes not the underlying biology of an illness, but the way a person experiences or reacts to an illness," Dr. Kaptchuk says.
University of Western Ontario researcher Dr. ChilYong Kang says "millions of lives" could be saved if a vaccine he developed is found to prevent the transmission of HIV. After 20 years of researching HIV/AIDS and 10 years trying to develop a vaccine, the virology professor has reached a key milestone - approval by the U.S. Food and Drug Administration to begin trials on humans... The process will take about five years.
Though the news was "very exciting," Michele Sharp, executive director of the AIDS Committee of Windsor, added a note of caution. "It is way too soon to know if this is something that is amazing or not." Right now, there's no proof it works on humans - that's what trials are for," said Sean Hosein, the science and medicine editor for CATIE, Canada's centre for information about HIV, hepatitis C and sexually transmitted infections. "I think it's a good idea to test, but it's in testing, so we don't know what will happen." Dr. Jonathan Angel, an infectious disease specialist who is president of the Canadian Association of HIV Research, said there are more than 100 FDA-approved trials for HIV vaccines. "To speculate this will be the answer is a little much," he said of Kang's vaccine. "But it's off to a good, but very, very early start." Kang said his is the first and only vaccine to use a genetically modified killed whole HIV virus. It employs the same proven approach used for polio, rabies, flu and hepatitis A vaccines, in which the actual virus is killed and introduced into the body, allowing the immune system to learn how to defend itself. Up to now, that method couldn't be tried with HIV because the virus could not be created in high enough quantities and because it was too dangerous to produce, said Kang. "And we solved that problem by genetically modifying the virus." The virus is then killed using chemicals and radiation... Kang said making his virus available in developing countries was his top demand when Korean pharmaceutical company Sumagen offered to invest in his research a number of years ago.
Advanced printing technologies could one day replace traditional blood and urine tests in hospitals. Scientists are pioneering a way to use ink and antibodies to test for illnesses such as HIV, prostate cancer or simple cholesterol tests. Tiny dots on a piece of paper could soon revolutionize the way diseases and other ailments are diagnosed, and save valuable time and money in the process. "We thought it would be a good idea to see if we could turn an expensive test for the hospital into a high volume test that could be possibly moved out to the point of care," said Tim Claypole, a research professor at Swansea University. Hospitals and doctors currently spend around $800 per test to collect blood samples and send them off to a lab. But by mixing ink with living antibodies and then printing them on plastic strips, tests can be conducted. Exposing the microdots to blood or urine samples will cause the dots to change colors. "Ultimately it could be a test that somebody in their own home could do. Certainly the move towards printed plastic electronics means that you could have a completely disposable sensor. So if a person was feeling unwell they could monitor their own condition," said Claypole. And for patients who are impatient about their health, the test strips could provide for much quicker diagnoses... More research needs to be carried out, but scientists say the strips could become as common as home diabetic blood monitors.
In the first clinical trial of an injectable vaccine containing trimeric HIV envelope protein (gp140) relevant to the predominant strain of HIV in Africa, researchers from four UK academic centers (St George's University London, Imperial College, Hull York Medical School (HYMS; University of York) and the Medical Research Council Clinical Trial Unit) and from the Infectious Disease Research Institute (IDRI) have come together to evaluate whether the vaccine is safe for use in human volunteers... The trial, which is funded by the Wellcome Trust and goes by the name MUCOVAC2, is evaluating a vaccine that contains the HIV trimeric gp140 protein CN54, representative of Clade C strains of the virus, the most prevalent type of virus in Sub-Saharan Africa and responsible for the greatest number of infections globally. The trimeric protein represents the major target for antibodies on the viral surface. The vaccine candidate will be formulated with an adjuvant known as GLA, developed by IDRI to enhance immune responsiveness following intramuscular injection. GLA formulations have been previously tested clinically with promising results...
MUCOVAC2, which is now screening potential participants, will enroll 36 healthy, HIV-negative women aged 18-45 years at St George's University of London and the HYMS Experimental Medicine Unit at York Hospital. Researchers will evaluate the vaccine's safety and determine the quality and magnitude of induced immune responses. The study is expected to take less than a year to complete with results available early 2013. Women will be randomly assigned to receive the vaccine by intramuscular injection, intranasal immunization through the application of liquid drops to the nose, or a combination of intramuscular injection followed by intravaginal immunization through the application of a gel-based formulation. This will enable researchers to compare the safety and levels of induced antibodies in the blood and vaginal secretions generated by the different vaccine approaches. Leading the study for St George's is Dr. Catherine Cosgrove, with Professor Charles Lacey leading the study at York... Our collaboration marks an important juncture for the field as we begin to assess which routes of immunization may provide the best responses to protect women," remarks professor Robin Shattock, who is chair in mucosal infection and immunity at Imperial College, and who leads the consortium which developed the MUCOVAC2 trial.
New HIV cases and AIDS deaths are both going steadily down in British Columbia, according to data released last week. "We're particularly pleased to see that our treatment-as-prevention strategy has taken off big-time," said Dr. Julio S. G. Montaner, director of the British Columbia Center for Excellence in HIV/AIDS. His center was a pioneer in the strategy, which involves searching aggressively for people at risk of HIV infection, talking them into being tested and putting those who are infected on antiretroviral drugs immediately, which lowers by 96 percent the chances that they will infect others. In Vancouver, where he works, AIDS is concentrated in two largely separate groups: gay men and drug addicts. To reach the addicts, the city opened a center where they can inject under a nurse's supervision without fear of arrest; the nurses also offer medical care, including tests. Testing is increasing, and syphilis rates are holding steady, Dr. Montaner said, so the drop in new cases is not a result of fewer tests or greater condom use. AIDS cases remain steady in Canada's other provinces, except for those in the Prairies region, where they tripled, mostly among Indian addicts in Saskatchewan, which has no safe-injection center. Last week, Science magazine named the treatment-as-prevention strategy, with the clinical trial of 1,763 couples on four continents that proved it worked, as its 2011 "Breakthrough of the Year." Dr. Montaner said he is frustrated that rich countries will not donate enough money to roll out the strategy in poor countries with huge HIV epidemics.
A vaccine against a monkey virus could offer clues to defeating HIV. Scientists have created a vaccine that protects rhesus monkeys from infection with a potent form of the simian immunodeficiency virus (SIV), which is distantly related to the virus that causes AIDS in humans. SIV vaccines have been successful before, but the protective effects have proved difficult to carry over to HIV. Scientists are hopeful that the latest results, which appear online in Nature today, can be combined with findings from a modestly successful vaccine trial in humans to point the way to an effective HIV vaccine... Because HIV does not cause disease in monkeys, SIV is the best model for evaluating vaccines before they are tested in humans, says Dan Barouch, a virologist at Beth Israel Deaconess Medical Center in Boston and the lead author of the latest paper... His team treated groups of rhesus monkeys (Macaca mulatta) with several different two-stage vaccines, made up of a 'prime' virus genetically engineered to contain SIV genes, followed half a year later by a 'boost' consisting of another virus expressing the same genes. Six months after the boost, Barouch's team infected monkeys with a strain of SIV that differed from the vaccine strain, and against which monkeys have trouble mounting a strong immune response. A vaccine made of an adenovirus prime and a modified-pox-virus boost was best at stopping infection... The animals that produced high levels of antibodies that attach to the 'envelope' protein that surrounds the virus were most impervious to infection. Different immune responses against the envelope and another SIV protein called Gag were found in animals that developed infection but kept the virus at low levels.
Other groups hoping to develop HIV vaccines will pay close attention to the findings. "They give us a blueprint for how we should move forward in vaccines to test and what kinds of responses we hope they'll induce," says Barouch. Some of those immune responses were also seen in the only HIV vaccine trial so far that has protected humans from infection, he notes. Researchers leading the RV144 trial (also known as the Thai trial) reported in 2009 that their combination vaccine reduced the odds of contracting HIV by about 30%. Trial subjects who did not contract HIV also tended to produce the highest levels of antibodies against HIV's envelope protein... Follow-ups to the RV144 trial are in the works, and Walker's team is raising money for a South African trial of an HIV vaccine equivalent to Barouch's SIV vaccine. "I think we need to make multiple shots on goal over the next few years," says Walker. Robin Weiss, a virologist at University College London, calls the study "an interesting advance," but he would like to see proof that the SIV vaccines protect against more than one SIV strain. Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland, says that the SIV study should be taken with "a grain of salt" because it was done in animals, not humans. But its results, when combined with those of the RV144 trial and other studies suggesting that some people can mount a vigorous immune response to HIV, give reason for optimism. "People generally feel we're going in the right direction," says Fauci.
The failure of a once-promising vaccine against the sexually transmitted herpes simplex virus has researchers struggling to determine the next step for the field. The vaccine contained a component called glycoprotein D, which is found in the envelope that surrounds herpes simplex virus 2 (HSV-2). Proteins on the surface of the envelope are important for enabling the virus to attach to and invade host cells. The hope was that the vaccine would stimulate the production of antibodies against glycoprotein D and prevent the virus from establishing an infection. But in a randomized, double-blind clinical trial involving 8,323 women, the vaccine did not prevent infection by HSV-2 -- although it did offer some protection against a closely related virus, HSV-1. The results, published today in The New England Journal of Medicine, are puzzling given the promising results shown by the vaccine in previous, smaller clinical trials. "It's very disappointing for the field," says Lawrence Corey, a virologist at the Fred Hutchinson Cancer Research Center in Seattle, Washington. "We know it failed, but we don't have a lot of insight as to why." Researchers are now ready to mine the latest results for clues to a better vaccine design, says Robert Belshe, a specialist in infectious diseases at St Louis University in Missouri and first author on the vaccine study. "It was a surprise," he says, "but it really guides us towards a future vaccine."
Where does that leave the field? "Enough vaccines have failed that companies are seeing herpes vaccines as a risky business," says David Knipe, a virologist at Harvard Medical School in Boston, Massachusetts. As a result, Knipe says that the public sector needs to step in to fill the gap. Some companies do still have a foothold in the field, however. Sanofi Pasteur, the vaccines division of Paris-based drug maker Sanofi, has licensed a vaccine candidate from Knipe's lab that is based on a live virus that is unable to replicate. And last year, Amgen, a biotechnology firm based in Thousand Oaks, California, purchased a small company called BioVex, of Woburn, Massachusetts, which is testing another vaccine that uses live, weakened HSV-2. Both vaccines are still in the early stages of testing, and will take years to develop. Meanwhile, Corey advocates going back to the basic biology of genital herpes, such as understanding the role of the immune system in the mucosa lining the genital tract. "We need to understand the immunobiology of HSV acquisition," he says. "What are the immune responses in the genital tract and how do we develop those immune responses through vaccination?" Ultimately, what the field needs is a workshop at which researchers can discuss where to go next, says Corey. "There has not been a conscious strategic plan [for HSV vaccines] by any funding agency or pharmaceutical company," he says. "Meanwhile, HSV continues to spread around the globe."
The Kenyan government has changed its HIV testing algorithm following the withdrawal of a widely used brand of HIV test on warnings from UN World Health Organization (WHO). In December, WHO removed the Standard Diagnostics Bioline HIV 1/2 3.0 Rapid HIV Test Kit from its list of approved rapid test kits with immediate effect; the alert was issued after Bioline failed quality assurance tests. The Kenyan government estimates one million kits were in circulation at the time of the recall, about one-tenth of all the HIV kits available in the country... Bioline, which is manufactured in South Korea, was in use as a confirmatory test, the second conducted during standard HIV testing, which uses three tests - an initial screening test, a confirmatory test and if there is a discrepancy, a third, tie-breaker test. As a result of the recall, Unigold, the brand used in Kenya as a tie-breaker, now replaces Bioline as the confirmatory test, and the enzyme-linked immunosorbent assay (ELISA) test - which requires a blood sample be sent to a laboratory and takes significantly longer than the rapid tests - becomes the tie-breaker.
A brand known as Determine retains its place as the official screening test. "We have already engaged the services of a supply chain management organization to help with collecting the Bioline kit from facilities countrywide and at the same time, replace it with Unigold... However, health workers are concerned that the use of the ELISA test will discourage nervous testers. There is also concern about the impact the recall will have on public confidence in HIV testing, especially as the country pushes for universal access to HIV counselling and testing.
In 2010, President Dmitry Medvedev said heroin was a threat to Russia's national security. This year, Russia pledged to finance programs to reduce the harm done by drug use, including an HIV crisis that is one of the most severe in the world. But even though the number of new HIV infections in Russia jumped 10 percent over 2011, health workers and global HIV authorities say Moscow has not honored that promise. This is not due to a lack of cash - Russia is doubling its budget for HIV in 2012 from 2010 levels. At issue is how it will use the funds. From next year, no money will go to such internationally recognized efforts as needle exchanges. None has ever gone to heroin substitution: the Russian authorities oppose it. Moscow doesn't believe these approaches help slow the spread of HIV/AIDS. "Working on drug dependency is more effective than needle exchange and methadone programs," said Alexei Mazus, who heads the Moscow Centre for HIV/AIDS Prevention, one of around 100 such venues across the country run by the health ministry.
In areas where needle exchanges have taken place, he said the health ministry had seen new HIV cases increase, not fall. Russia's health ministry said last year it had evidence that HIV rates have tripled in areas where foreign-run needle exchange programs were running. The United Nations says so-called "harm reduction" programs - needle exchanges, and using methadone as a substitute for heroin - are effective in slowing the spread of HIV. Methadone reduces the risk of infection by dirty needles because it can be swallowed, rather than injected. A major WHO study found HIV rates fell more than 18 percent in cities with needle exchanges, while they rose 8 percent in areas that did not have them. The British and U.S. governments both approved needle exchanges in recent drug policies drafted to combat HIV. But in Russia's drug strategy for 2010-20, heroin substitutes are banned. Projects such as giving drug users and sex workers clean needles, HIV awareness training and medication have been funded by the United Nations in Russia for the last seven years. Next year that funding comes to an end and with it, so will most of these schemes. Some health workers and global HIV authorities are angered and baffled by Russia's approach, which they say will only aggravate the problem...
The hunt has begun to identify 100 volunteers belonging to a rare group of HIV infected patients who stay healthy for years without requiring life-saving antiretroviral treatment (ART)... This is part of International Aids Vaccine Initiative's (IAVI) programme called Protocol G, a global hunt for such antibodies launched in 2006. So far, blood samples of 1,800 such HIV patients have been screened across 12 countries and 19 broadly neutralizing antibody (bNAbs) have been identified. A bNAb is an antibody capable of stopping a variety of HIV subtypes from infecting their target cells. "Only a minority of people who are infected with HIV produce bNAbs. Although HIV is a wildly mutable virus, certain parts of it are relatively resistant to change. These parts are essential to the virus's ability to infect, and they are the elements of HIV that bNAbs target," experts said.
Just a few weeks ago, department of biotechnology (DBT) cleared the proposal to roll out Protocol G in the country. It is being implemented by IAVI and YRG Care from Chennai - the same organization that isolated the first HIV case in India in 1986. The blood samples collected from the 100 volunteers will be tested at Translational Health Sciences and Technology Institute (THSTI), which is being built in Gurgaon. IAVI's India chief Dr Rajat Goyal told TOI that "This is a landmark project for India. We are presently identifying volunteers, who are at least 18 years, infected with HIV at least three years ago but have not received ART. By April, samples will be picked up and tested against a standard panel of HIV isolates by the end of 2012. We will then know whether there is a population of interest from whom these bNAb can be identified and characterized." Careful study of bNAbs is expected to reveal vulnerabilities of the different types of HIV. Most importantly, scientists expect that they can use information about how bNAbs bind to HIV to construct immunogens - the active ingredients of vaccines - that elicit similar antibodies. The more such antibodies researchers have in hand, the more clues they can get about how best to target HIV with a vaccine. The project has tested HIV patients in Thailand, the UK, the US, Nigeria, South Africa, Rwanda, Uganda, Kenya, Australia and Zambia to identify bNAbs.
Since 2007, Ontario has offered free human papillomavirus vaccine to eighth-grade girls, but a new study suggests that adding a catch-up program for women ages 17-26 would result in additional cost savings and health gains. The study analyzed whether a catch-up HPV program for women missed by the school-based campaign made economic sense. The school-based program uses Merck's Gardasil vaccine, which targets four HPV strains. The analysis presumed the older women would receive GlaxoSmithKline Cervarix, which protects against two HPV types responsible for most cervical cancer cases. Senior study author Chris Bauch, who is with the mathematics and statistics department at the University of Guelph in Ontario, said it appears the adjuvant-boosted Cervarix may be more effective in older women. Annually, a catch-up program would save nearly $19 million (US $18.8 million) and 240 years of life for women who would not go on to die of cervical cancer, the study found. In conjunction with a catch-up program, the researchers also proposed delaying women's initial Pap smear from the currently recommended age of 18 to age 25. Delaying the exam would not jeopardize lives overall, the study suggests."Basically you're stopping a program that doesn't prevent a lot of cancer, (a) because there isn't a lot of cancer in younger ages and (b) because the screening is actually not very exact," Bauch said. "And you're taking the money you save on that relatively inefficient program and putting it into the vaccine, which can prevent more cancer more effectively than the screening program, according to the model." However, physicians often use the initial Pap visit to discuss other health services, such as birth control, Bauch said, so doctors would have to find other opportunities to offer these services. The study, "Time for Change? An Economic Evaluation of Integrated Cervical Screening and HPV Immunization Programs in Canada," was published in Vaccine (2012;30(2):425-235).
A new study shows a decline in reproductive health care use among US females ages 15-24 in recent years. The researchers, led by Kelli Stidham Hall of Princeton University's Office of Population Research, examined data on 4,421 young female participants in the National Survey of Family Growth. The team found an 8 percent drop in the women's reports of Pap tests, screenings for STDs and pregnancy, and other OB-GYN services from 2002 to 2006-08. By comparison, reproductive health care use among young women increased between 1995 and 2002, the team noted. While declines were seen among all demographic and socioeconomic groups, economically disadvantaged women were the least likely to have received care. Factors that may have contributed to the downturn in use include: a reduction in public-sector clinics serving low-income women; increasing unemployment and decreasing rates of health insurance coverage; changes to screening guidelines that call for fewer Pap tests; and legislation that has increased mandatory parental participation in adolescent sexual and reproductive health care. "Our findings may be a reflection of changing social, economic, and political contexts in which reproductive services were needed and provided over the last decade," wrote the team. "Determinants of and Disparities in Reproductive Health Service Use Among Adolescent and Young Adult Women in the United States, 2002-2008," was published online ahead of print in the American Journal of Public Health.
Very little information exists with regard to sex party behaviors in young men who have sex with men (YMSM), often defined as men ranging in age from 13 to 29 years. The current analysis examines sex party attendance and behavior in a sample of 540 emergent adult gay, bisexual, and other YMSM in New York City, ages 18-29 years. Findings indicate that 8.7% (n=47) of the sample had attended a sex party 3 months prior to assessment. Sex party attendees reported that parties included both HIV-positive and HIV-negative men; attendees also reported unprotected sex and limited access to condoms and lubricant. As compared with those who did not attend sex parties, those who did indicated significantly more lifetime and recent (last 3 months) casual sex partners, drug use (both number of different drugs used and total lifetime use), psychosocial burden (history of partner violence and number of arrests), and total syndemic burden (a composite of unprotected anal sex, drug use and psychosocial burden). These results indicate that while only a small percentage of the overall sample attended sex parties, the intersection of both individual risk factors coupled with risk factors engendered within the sex party environment itself has the potential to be a catalyst in the proliferation of the HIV/AIDS epidemic in urban settings. Lastly, given that sex parties are different than other sex environments, commercial and public, with regard to how they are accessed, public health strategies may need to become more tailored in order to reach this potentially highly risky group.
Abstract Background: Two previous studies of a herpes simplex virus type 2 (HSV-2) subunit vaccine containing glycoprotein D in HSV-discordant couples revealed 73% and 74% efficacy against genital disease in women who were negative for both HSV type 1 (HSV-1) and HSV-2 antibodies. Efficacy was not observed in men or HSV-1 seropositive women.
Methods: We conducted a randomized, double-blind efficacy field trial involving 8323 women 18 to 30 years of age who were negative for antibodies to HSV-1 and HSV-2. At months 0, 1, and 6, some subjects received the investigational vaccine, consisting of 20 ug of glycoprotein D from HSV-2 with alum and 3-O-deacylated monophosphoryl lipid A as an adjuvant; control subjects received the hepatitis A vaccine, at a dose of 720 enzyme-linked immunosorbent assay (ELISA) units. The primary end point was occurrence of genital herpes disease due to either HSV-1 or HSV-2 from month 2 (1 month after dose 2) through month 20.
The HSV vaccine was associated with an increased risk of local reactions as compared with the control vaccine, and it elicited ELISA and neutralizing antibodies to HSV-2. Overall, the vaccine was not efficacious; vaccine efficacy was 20% (95% confidence interval [CI], -29 to 50) against genital herpes disease. However, efficacy against HSV-1 genital disease was 58% (95% CI, 12 to 80). Vaccine efficacy against HSV-1 infection (with or without disease) was 35% (95% CI, 13 to 52), but efficacy against HSV-2 infection was not observed (-8%; 95% CI, -59 to 26).
In a study population that was representative of the general population of HSV-1 and HSV-2 seronegative women, the investigational vaccine was effective in preventing HSV-1 genital disease and infection but not in preventing HSV-2 disease or infection.
Preclinical studies of human immunodeficiency virus type 1 (HIV-1) vaccine candidates have typically shown post-infection virological control, but protection against acquisition of infection has previously only been reported against neutralization-sensitive virus challenges. Here we demonstrate vaccine protection against acquisition of fully heterologous, neutralization-resistant simian immunodeficiency virus (SIV) challenges in rhesus monkeys. Adenovirus/poxvirus and adenovirus/adenovirus-vector-based vaccines expressing SIV SME543 Gag, Pol and Env antigens resulted in an 80% or greater reduction in the per-exposure probability of infection against repetitive, intrarectal SIV MAC251 challenges in rhesus monkeys. Protection against acquisition of infection showed distinct immunological correlates compared with post-infection virological control and required the inclusion of Env in the vaccine regimen. These data demonstrate the proof-of-concept that optimized HIV-1 vaccine candidates can block acquisition of stringent, heterologous, neutralization-resistant virus challenges in rhesus monkeys.
Recent years have seen growing worldwide discussions, experiments, and expectations around various kinds of public engagement in the biosciences. This is especially so, in the governance of biotechnology--in research policy, risk regulation, and adoption of new innovations. How one defines public engagement necessarily affects the course of political, media, and civil society debate on these issues. Yet critics and even some proponents often misunderstand underlying rationales and imperatives for engagement. Strong opposition persists on the part of some policymakers in the ostensible name of science, even to the most modest forms of citizen participation in decisions about regulation or research. Where dialogue is supported between scientists, policy makers, stakeholders, and members of the public, it is often for contrasting reasons--reflecting motivations of some leading figures in science governance to control, as much as respect, contending public interests. Prominent experts have questioned whether ordinary people have the right or even the ability to engage on complex technical issues. Attempts to include stakeholders are criticized as slowing down innovation. Some scientists fear that irrational anxieties over particular issues mean that public engagement will lead to indiscriminately technophobic or anti-science results. How might we interpret these attitudes and controversies and better understand why public engagement matters? What are the practical policy consequences?
This paper identifies different grounds for supporting particular elements of public engagement, irrespective of context. It describes how diverse qualities of participatory practice arise in different circumstances. The starting point is that the realities of technological change--particularly as they relate to policy making--demand a move away from traditional exclusive, specialist approaches. This means relinquishing the blanket pro-innovation rhetoric used by many in high-level policy making: portraying technological progress as ... a "race to advance technology"--a single track to an essentially inevitable future. This linear notion conceals the continually branching nature of technological change. It hides the ways important political choices over alternative directions for innovation are made at every juncture--and should be as subject as other areas of policy, to democratic participation and accountability. In this sense, then, various kinds of public engagement in the biosciences can be seen to offer means to reconcile tensions between the otherwise-estranged Enlightenment values of science and democracy. In short, greater public engagement offers an opportunity to be more rigorous about the uncertainties in bioscience innovation and more accountable about the exercise of power...
Despite tremendous efforts, development of an effective vaccine against human immunodeficiency virus (HIV) has proved an elusive goal. Recently, however, numerous antibodies have been identified that are capable of neutralizing most circulating HIV strains. These antibodies all exhibit an unusually high level of somatic mutation, presumably owing to extensive affinity maturation over the course of continuous exposure to an evolving antigen. Although substantial effort has focused on the design of immunogens capable of eliciting antibodies de novo that would target similar epitopes, it remains uncertain whether a conventional vaccine will be able to elicit analogues of the existing broadly neutralizing antibodies. As an alternative to immunization, vector-mediated gene transfer could be used to engineer secretion of the existing broadly neutralizing antibodies into the circulation. Here we describe a practical implementation of this approach, which we call vectored immunoprophylaxis (VIP), which in mice induces lifelong expression of these monoclonal antibodies at high concentrations from a single intramuscular injection. This is achieved using a specialized adeno-associated virus vector optimized for the production of full-length antibody from muscle tissue. We show that humanized mice receiving VIP appear to be fully protected from HIV infection, even when challenged intravenously with very high doses of replication-competent virus. Our results suggest that successful translation of this approach to humans may produce effective prophylaxis against HIV.
Articles published in BMJ and PLoS Medicine call for greater transparency in clinical trials through increased sharing of information. The BMJ editorial accompanies a cluster of research papers that show, despite regulatory pressure, many clinical trials fail to report data in a timely manner. "This is no academic matter, because missing data about harm in trials can harm patients, and incomplete data about benefit can lead to futile costs to health systems", Richard Lehman, of University of Oxford, and Elizabeth Loder, of BMJ, wrote. In 2007 the US Food and Drug Administration (FDA) Amendments Act made publication of summary results on ClinicalTrials.gov mandatory within one year. An analysis of ClinicalTrials.gov published by BMJ yesterday found 40 per cent of industry funded trials had reported results. The BMJ editorial calls for stronger enforcement to encourage data reporting. "Concealment of data should be regarded as the serious ethical breach that it is, and clinical researchers who fail to disclose data should be subject to disciplinary action by professional organisations", Lehman and Loder wrote. A paper in PLoS Medicine tackles transparency earlier in the process by calling for all investigators' patient recruitment targets to be published on ClinicalTrials.gov before a study begins. The authors of the paper, who include a former GlaxoSmithKline employee and an advisor to the Spanish Medicines Agency, also want information on issues that could affect recruitment to be shared. "We propose for a given site, that if the trial has more than one recruiting principal investigator, then information for all recruiting investigators should be provided", the authors wrote. Access to this data could help sponsors "recruit investigators with a track record of fulfilling their commitments".
Evidence from biological, epidemiological, and controlled intervention studies has demonstrated that male circumcision (MC) protects males from HIV infection, and MC is now advocated as a public-health intervention against HIV. MC provides direct protection only to men, but is expected to provide indirect protection to women at risk of acquiring HIV from heterosexual transmission. How such indirect protection interacts with the possibility that MC campaigns will lead to behavior changes, however, is not yet well understood. Our objective here is to investigate the link between individual-level effects of MC campaigns and long-term population-level outcomes resulting from disease dynamics, looking at both genders separately, over a broad range of parameters.
Methods and Findings:
We use simple mathematical models of heterosexual transmission to investigate the potential effects of a circumcision scale-up, combined with possible associated behavioral disinhibition. We examine patterns in expected long-term prevalence using a simple equilibrium model based on transmission factors, and validate our results with ODE-based simulations, focusing on the link between effects on females and those on males. We find that the long-term population-level effects on females and males are not strongly linked: there are many possible ways in which an intervention which reduces prevalence in males might nonetheless increase prevalence in females.
Since an intervention that reduces long-term male prevalence could nonetheless increase long-term female prevalence, MC campaigns should explicitly consider both the short-term and long-term effects of MC interventions on females. Our findings strongly underline the importance of pairing MC programs with education, support programs and HIV testing and counseling, together with other prevention measures.
People resist medical screening, or don't call back for the results, because they don't want to know they're sick or at risk for a disease. But many illnesses, such as HIV/AIDS and cancer, have a far a better prognosis if they're caught early. How can health care providers break down that resistance? Have people think about what they value most, finds a new study by University of Florida psychologists Jennifer L. Howell and James A. Shepperd. "If you can get people to refocus their attention from a threat to their overall sense of wellbeing, they are less likely to avoid threatening information," says Howell. Do that, and people are more likely to face a medical screening even if it means undertaking onerous treatment and even if the disease is uncontrollable. The findings will appear in Psychological Science, a journal published by the Association for Psychological Science...
Howell JL, Shepperd JA. Reducing information avoidance through affirmation. Psychological Science, (in press).
Science has chosen the finding that antiretroviral drugs reduce the risk of heterosexual transmission of HIV as its Breakthrough of the Year. On 1 December, George Washington University in Washington, D.C., hosted "The Beginning of the End of AIDS," a splashy World AIDS Day event that featured three U.S. presidents, business magnates, and rock stars. The catalyst that brought them together was something Anthony Fauci, the top U.S. government HIV/AIDS scientist, told the crowd even 1 year ago would have seemed "wishful thinking": a clinical trial dubbed HPTN 052 and its "astounding" result. HIV/AIDS researchers have long debated whether antiretroviral drugs (ARVs) used to treat HIV-infected people might have a double benefit and cut transmission rates. To some it was obvious: ARVs reduce HIV levels, so individuals should be less infectious. Skeptics contended that this was unproven. Indeed, a consensus statement issued by the Swiss Federal Commission for HIV/AIDS in 2008 that said effective ARV treatment could virtually stop heterosexual transmission was denounced as "appalling," inconclusive and irresponsible," "dangerous," and "misleading." The Joint United Nations Programme on HIV/AIDS and the World Health Organization also responded with alarm, urging people to continue using condoms and stressing that semen or vaginal secretions might harbor the virus even when blood tests showed no trace of it. "More research is needed to determine the degree to which the viral load in blood predicts the risk of HIV transmission," they cautioned.
Then in May of this year, the 052 clinical trial conducted by the HIV Prevention Trials Network reported that ARVs reduced the risk of heterosexual transmission by 96%. "Now we have absolute, confirmed data," said Fauci at an AIDS conference this summer in Rome where researchers first presented the HPTN 052 data in detail. Fauci, who heads the U.S. National Institute of Allergy and Infectious Diseases--the main funder of the $73 million trial--said the challenge now was to apply the results. "We just need to take that data and run with it," he said. "The idea of the tension between treatment and prevention, we should just forget about it and just put it behind us, because treatment is prevention." Because of HPTN 052's profound implications for the future response to the AIDS epidemic, Science has chosen it as its Breakthrough of the Year...
To (1) examine perceptions of risk of human papillomavirus (HPV) and other sexually transmitted infections (STIs), (2) examine perceived need for safer sexual behaviors, and (3) determine factors associated with less perceived need for safer sexual behaviors, all in the context of receiving the first HPV vaccination.
Cross-sectional baseline analysis from an ongoing longitudinal cohort study.
An urban hospital-based adolescent primary care clinic.
Girls 13 to 21 years (for this article girls are defined as being aged 13 to 21 years) (n=339) receiving their first HPV vaccination and their mothers (n=235).
Main Outcome Measures:
(1) Girls' perceived risk of HPV after HPV vaccination, (2) girls' perceived risk of other STIs after vaccination, (3) girls' perceived need for continued safer sexual behaviors after vaccination, and (4) factors associated with girls' perception of less need for safer sexual behaviors.
Mean age of girls was 16.8 years. Most participants (76.4%) were black, and 57.5% were sexually experienced. Girls perceived themselves to be at less risk for HPV than for other STIs after HPV vaccination (P < .001). Although most girls reported continued need for safer sexual behaviors, factors independently associated with perception of less need for safer sexual behaviors included adolescent factors (lower HPV and HPV vaccine knowledge and less concern about HPV) and maternal factors (lower HPV and HPV vaccine knowledge, physician as a source of HPV vaccine information, and lack of maternal communication about the HPV vaccine).
Few adolescents perceived less need for safer sexual behaviors after the first HPV vaccination. Education about HPV vaccines and encouraging communication between girls and their mothers may prevent misperceptions among these adolescents.
Gladstone Institutes scientist Nevan Krogan, PhD, has identified how HIV -- the virus that causes AIDS -- hijacks the body's own defenses to promote infection... In his companion papers being published online in Nature, Dr. Krogan describes how HIV commandeers restriction factors -- a class of human proteins that have evolved to block viruses such as HIV -- to weaken the body's defenses and enhance the virulence of HIV infection...
In his experiments, Dr. Krogan performed a two-part investigation of protein interactions. First, he conducted a systematic, global analysis of all potential interactions that occur between proteins made by the body (human proteins) and proteins made by the virus (HIV proteins). Second, he whittled down these ~500 interactions to the one that appeared most likely to fuel HIV infection: the interaction between the human protein CBF(beta) and the HIV protein Vif. Normally during HIV infection, a restriction factor called APOBEC3G acts as a molecular roadblock, preventing the virus from reaching its target -- the CD4 T white blood cells that are a major component of the immune system. But Dr. Krogan found that when the HIV protein Vif binds to the human protein CBF(beta), Vif is strengthened and APOBEC3G degrades. This degradation weakens ABOBEC3G's ability to stop HIV and the virus is free to infect the CD4 T cells. "This is the first comprehensive look at how HIV interacts globally with components of the cell," said Judith H. Greenberg, PhD, acting director of the National Institutes of Health's National Institute of General Medical Sciences, which partially supported this research through its AIDS-related structural biology program. "The work is a good example of how biophysical studies can improve our understanding of disease and point the way to the exploration of potential therapeutic targets."
To characterize the correlates of protection from systemic infection in a vaccinated rhesus macaque, RAt-9, which had been challenged sequentially with two related clade C simian/human immunodeficiency viruses (SHIV-Cs) yet remained aviremic for more than 5 years despite indirect evidence of cryptic infection.
To measure long-term anti-SHIV-C immunity, host genetics and gene-expression patterns for protective correlates.
Long-term immune reactivity was evaluated and identification of virus in RAt-9 was attempted by RT-PCR analysis of concentrated plasma and blood transfer to CD8+ cell-depleted infant macaques. Full MHC genotyping of RAt-9, TRIM5(alpha) and KIR3DL allelic expression analysis of PBMC, and microarray gene expression analysis were performed.
All attempts to detect/isolate virus, including blood transfer to CD8+ cell-depleted infant rhesus macaques, were negative, and the animal maintained normal levels of memory CD4+ T cells in both peripheral blood and gut tissues. However, RAt-9 maintained high levels of anti-SHIV-C humoral and cellular immunity, including reactivity to nonvaccine neoantigens (Nef and Rev), up to 63 months postinitial challenge, suggesting chronic sub-threshold infection. RAt-9 expressed the Mamu A*001 allele negative for B*008 and B*017, had a B13 serotype, and had increased expression of killer-cell immunoglobulin-like receptors (KIRs) previously linked to favorable outcomes of lentiviral infection. Elements of the gene expression profiling coincided with genotyping results. RAt-9 also displayed CD8+ cell noncytotoxic antiviral response (CNAR) activity.
Monkey RAt-9 is the first example of a virus-exposed, persistently aviremic animal that has maintained long-term, high-level cellular and humoral antiviral immunity in the absence of an identifiable cryptic reservoir.
Recent HIV prevention trials have given hope that a suite of interventions that effectively reduce individuals' risk of HIV infection will soon be widely available. In two studies, the RV144 and CAPRISA 004 trials, the relative risk of infection increased toward the null value of one over time. The RV144 and CAPRISA investigators interpreted these trends as evidence that the interventions' effects declined over the study period and suggested that their respective findings may be explained by waning vaccine efficacy and decreasing adherence. Here, we discuss these trends in the trials' results and note that, in addition to the possible mechanisms cited by the investigators, their apparent waning efficacy may be explained in part by selection bias due to heterogeneity in infection risk, an explanation that has not been considered previously. This bias arises when study participants vary in their susceptibility to infection, for example, because of differences in immune systems or exposure to infection. This can lead to increasing differences in the composition of the study population in each trial arm over time as those at highest risk become infected, and can occur despite comparability between arms at baseline. This issue is termed 'frailty' in statistics and demography, in which a large body of literature addresses the matter. We also discuss several methods that can improve understanding of the effects of infectious disease interventions and risk factors by assessing the impact of frailty on results...
Compelling new evidence showing that oral antiretroviral drugs (ARVs) can prevent heterosexual HIV transmission has recently burst upon us... Are ARVs a magic bullet to stop the global epidemic in its tracks? It is not that simple. First, two additional trials of oral PrEP failed to show an impact. Moreover, such trials are conducted under optimal conditions designed both to maximize proper use of ARVs and to reduce risky behavior. Achieving an impact of ARVs at the population level is quite another matter. HIV is an elusive enemy, and a variety of major logistical, cost, biologic, and behavior impediments stand in the way of broad impact at scale...
Oral ARVs definitely have a supporting role to play in prevention as part of a combination approach based on every tool we can muster. Such tools include male circumcision, condoms, partner limitation, behavior change, and needle exchange working in synergy. But we need to proceed selectively and incrementally and to gather more evidence. Priority for treatment should be given to those with advanced disease who are as yet untreated. They would benefit clinically and provide greater prevention impact because their lower CD4 counts and higher viral load make them substantially more likely to transmit infection. Some modeling suggests high levels of ARV coverage in a few key countries may be reducing transmission. Other priorities include individuals more likely to transmit HIV, such as sex workers, and a partner in an identified discordant couple regardless of CD4 count. Women identified during pregnancy who successfully take ARVs to prevent vertical transmission could also be a priority. These priorities align with a recent President's Emergency Plan for AIDS Relief (PEPFAR) advisory. At the same time, we need to strengthen behavioral risk reduction and adherence for these high-priority individuals to avoid compromising ARV's prevention benefit. We do not know the extent to which findings in small-scale trials will extend to large-scale implementation. Some 50 studies on ARVs as prevention are under discussion, of which at least four are in larger study populations. Such research should inform any major expansion of ARVs as prevention. We also need better, cheaper, longer-acting, more user-friendly, and program-friendly ARVs for treatment and prevention.
A detailed examination of immune responses to a failed HIV vaccine candidate has turned up another stumbling block on the road to a successful immunization strategy, researchers reported. Having no antibodies to a viral vector intended to present HIV antigens to the immune system doesn't rule out a cellular immune response, according to Juliana McElrath, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues. And that can be enough to lower the response to the HIV antigens, McElrath and colleagues reported in the January issue of the Journal of Clinical Investigation. The finding is part of the continuing analysis of what went wrong with the so-called MRKAd5 vaccine candidate, which not only was not effective but actually increased the risk of acquiring HIV. To understand exactly why the vaccine failed, McElrath and colleagues analyzed samples from participants in the STEP clinical trial of the substance, which was halted early, as well as from participants in a parallel study. The viral vector was adenovirus serotype 5 -- or Ad5 -- which, when including HIV gene inserts, was able to induce strong HIV-specific cellular immune responses in preliminary studies.
In earlier analyses of the STEP trial, researchers found that a high level of neutralizing antibodies to the vector had a dampening effect on the cellular immune response to the HIV antigens. That suggested that rarer adenoviruses -- Ad36 and Ad24, for instance -- might be more suitable vectors, since they presumably would be less likely to encounter neutralizing antibodies when used in people, McElrath and colleagues noted. But a key finding of the current study, they reported, is that it's not just antibodies that depress the HIV-specific reaction. Instead, a higher pre-immunization frequency of adenovirus-specific CD4-positive T cells -- regardless of the presence or absence of Ad5 antibodies -- was associated with a substantially decreased magnitude of HIV-specific CD4 cell responses. Specifically, a 0.1% increase in the frequency of adenovirus-specific CD4 cells before vaccination was associated with a 0.04% decrease in the magnitude of HIV-specific CD4 cell responses a year later. The finding was significant at P=0.03. Even in study participants who did not have Ad5 antibodies, adenovirus-specific T cells were readily obtained, they reported. In the STEP trial, 54% of Ad5-seronegative placebo patients and 74% of those with Ad5 antibodies had such cells. What's more, adenovirus-specific CD4 cells recognized a set of proteins that were common to many different types, suggesting that switching to rare serotypes for future vaccine candidates may not be a workable strategy, McElrath and colleagues concluded. Although the exact mechanism of the dampening effect remains unclear, they argued, "our work may have broad implications for the use of (adenovirus) vectors in HIV vaccines." Evaluating the impact of preexisting immunity to the vector, they concluded, will need study of both the antibody response to the specific serotype and the T-cell response to adenoviruses in general.
Frahm N, DeCamp AC, Friedrich DP, Carter DK, et al. Human adenovirus-specific T cells modulate HIV-specific T cell responses to an Ad5-vectored HIV-1 vaccine. Journal of Clinical Investigation 2012; 122(1): 359--367.
HIV incidence is high among gay men who use post-exposure prophylaxis (PEP), investigators from Amsterdam report in the online edition of AIDS. Overall, users of PEP were almost four times more likely to become infected with HIV than gay men who did not use the therapy. There was no evidence that PEP failure was the cause. The investigators believe this is because PEP users continued to put themselves risk of HIV after completing their treatment. "Our study showed a high incidence of HIV among MSM [men who have sex with men] who used PEP, an indication of ongoing risk behaviour," write the investigators. "This implies that PEP alone for this group is not sufficient to prevent HIV infection, and a combination of other more comprehensive preventative strategies is needed."
HIV post-exposure prophylaxis is a four-week course of combination antiretroviral therapy, prescribed after an encounter with body fluids possibly infected with HIV. It is estimated that the treatment can reduce the risk of infection by up to 81%. Gay men are the group most likely to request PEP after a possible sexual exposure to HIV. Australian research has shown that gay men who used PEP continued to be at risk of HIV after completing their treatment. Therefore, Dutch investigators compared HIV incidence among gay men prescribed PEP in Amsterdam between 2000 and 2009, and compared this to the rate of new infections seen over the same period among gay men enrolled in the Amsterdam Cohort Study. A total of 355 men who received 395 PEP prescriptions were included in study. The majority of individuals took one course of PEP, but approximately 10% of men were provided with multiple prescriptions (two to four). Adherence rates were high, with 94% of men completing their therapy. HIV status was monitored three and six months after baseline. Eleven PEP users seroconverted. Two men tested HIV-positive at their three-month follow-up appointment; one individual who did not attend for his three month appointment was diagnosed at month six; and the remaining eight men were HIV-negative at month three, but were HIV-positive at month six. This provided an HIV incidence of 6.4 per 100 person years among the individuals treatment with PEP.
Heuker J Sonder JB, Stolte I, Geskus R, et al. High HIV incidence among MSM prescribed postexposure prophylaxis in Amsterdam, 2000-2009: indications of ongoing sexual risk behaviour. AIDS 25, online edition. 2011.
Guest Editor Patrick F. Kiser, PhD, University of Utah, is organizing a special issue of AIDS Research and Human Retroviruses dedicated to Microbicide Research and Therapeutics. All papers will be published online 72 hours after acceptance; final online and print issue scheduled for summer 2012. High-quality review articles and original articles are being sought on the following topics:
-Preclinical in vitro models
-Research in primates
-Pharmacokinetics and pharmacodynamics
-Efficacy and clinical trials
-Oral pre-exposure prophylaxis
-Independent measures of adherence
-Interface of microbicides and HIV vaccines
-New targets and small molecules
Deadline for manuscript submission: April 1, 2012.
Papers should be submitted online.