By Regina McEnery
Rallying for research
Volunteers from more than 175 medical research organizations rallied April 8 in Washington, D.C., to urge lawmakers to shield public health and scientific research from sweeping spending cuts that are likely to cripple several government programs in the US. As it happens, that’s two days before President Obama is scheduled to release his budget for fiscal year 2014.
The rally started at 11 a.m. on the Carnegie Library Grounds of Mt. Vernon Square and ran for a little more than an hour. Regan Hoffman, an AIDS activist and former editor of POZ magazine, was one of the speakers addressing the protestors, and several HIV/AIDS organizations, including The Foundation for AIDS Research (amfAR), HIV Medicine Association, and AIDS Action Baltimore were there as well. (For a full list of participants, visitwww.rallyformedicalresearch.org; and for a report on the rally, visit the IAVI Report blog.)
Federal agencies are still shakily coming to grips with the automatic spending cuts—a.k.a. sequestration—which took effect March 1 and will indiscriminately slash US$85 billion from government programs this year. Their bean-counters have been busy ever since, working out how to make ends meet: the US Federal Aviation Administration announced plans to shut down 146 of 516 air traffic control towers beginning April 7, and the National Parks Service is all set to close visitor’s centers and rest rooms, furlough park police, and hire fewer seasonal workers this summer.
Researchers and service providers across the country, meanwhile, are bracing for changes to their grants and contracts from the US National Institutes of Health, which stands to lose about $1.5 billion of its $31 billion annual budget (see IAVI Report March 5, 2013 blog, Sequester Overshadows Science). According to the NIH, many researchers whose grants aren’t dropped outright can expect painful cuts in funding, and financing for new grants and cooperative agreements will be extremely tight.
“The immediate impact is still being sorted out,” said Chris Collins, vice president and director of public policy at amfAR. “Over the long run, I am concerned that we are sleepwalking into an era of austerity. I think we all need to be speaking out about the importance of health investment right now.”
The human cost could be considerable. In a policy brief assessing the potential impact of cuts in global HIV/AIDS funding, amfAR suggested that sequestration would deprive 273,000 HIV-infected people from low-income countries of access to life-prolonging antiretroviral therapy, and curtail antiviral drugs and services for 111,000 HIV-infected pregnant women, which in turn could lead to 21,000 infants being infected with HIV.
Since the cuts took effect, committees from both the US House of Representatives, which is controlled by the Republicans, and the US Senate, nominally controlled by the Democrats, have submitted competing budgets for FY2014. They offer vastly different visions for the country. The Republican bill slashes government spending by $4.6 trillion over the next decade, including steep cuts in domestic programs and a 10% reduction in the federal workforce. The Senate version offers $1.85 trillion in deficit reduction through a mix of spending cuts and revenue increases. The House bill assumes the cuts dealt by sequestration will stay, while the Senate bill rolls them back. “Obviously, there is much better news for health research in the Senate proposal,” said Collins. “But we’re really waiting to hear from the President.”
The rally is aimed at both citizens and lawmakers, according to Collins. “This is an opportunity to say health research has tangible benefits for real people and there is great opportunity in the future to accomplish much more in terms of curing disease and advancing health. But to do this we can’t divest from our investment in health research.”
Heedless divestment, however, is the likely outcome in the absence of some coherent Congressional response—the probability of which is minute, regardless of what happened at Mt. Vernon Square.
New digs for The Ragon Institute
The Ragon Institute of Massachusetts General Hospital (MGH), the Massachusetts Institute of Technology (MIT), and Harvard has moved into a 216,000-square-foot building a few blocks from MIT, the Broad Institute, and the Whitehead Institute. Redevelopers recently transformed the building from a nine-story office facility into a 10-story laboratory and office complex. Along with The Ragon Institute, which occupies three-and-a-half floors, the building currently has three other tenants: Epizyme, Warp Drive Bio LLC, and Aramco Services.
The Ragon Institute, a rather unusual collaboration of engineers, doctors, and biologists headed by MGH AIDS and TB researcher Bruce Walker, was created with a US$100 million gift from Phillip “Terry” Ragon and his wife Susan. Its mission is to explore how the immune system combats disease, with an initial objective of developing an AIDS vaccine. Terry Ragon, founder of the Cambridge-based international software company InterSystems, became drawn to the field of AIDS vaccines after meeting Walker and hearing about his work (see In With The New…, IAVI Report, Jan.-Feb. 2009).
The Ragon Institute’s new space includes a vivarium and a Biosafety Level 3 lab, which will enable Ragon researchers to study TB in conjunction with HIV for the first time. The new space also includes a private phlebotomy room, the 160-seat Mark and Lisa Schwartz Auditorium—named for another major Ragon donor—and a large flow cytometry lab.
First Candidate HIV vaccine to employ Sendai vector poised for trials
The first Phase I trial to test the safety and immunogenicity of a novel Sendai vector-based vaccine candidate got underway in Rwanda on April 1 and is expected to begin soon in the UK and Kenya. The SeV-G (NP) vector, so named because it carries the HIV gag gene as its immunogen, will be evaluated in prime-boost combination with an adenovirus (Ad) serotype 35 vector candidate named Ad35-GRIN.
Derived from the Sendai virus—which belongs to the Paramyxoviridae family of viruses that includes the measles, canine distemper and human parainfluenza viruses (hPIV)—the SeV-G(NP) candidate retains the ability to replicate following vaccine delivery. Though Sendai causes a respiratory tract illness in rodents, it is not known to cause human disease.
This is only the fourth time that a replicating vector has been evaluated in clinical trials. A replicating vaccinia vector (based on the Tiantan strain) was tested in a Phase I trial in China several years ago (see Raft of Results Energizes Researchers, IAVI Report, Sep.-Oct. 2009), and a replicating measles vector was used in a Phase I study in Belgium. In addition, a vesicular stomatitis virus is being used in an ongoing study in the US.
The Ad35-GRIN candidate, meanwhile, has been evaluated in three clinical trials, and has been found to be safe and well tolerated so far. It carries as HIV immunogens the genes for HIV clade A gag, reverse transcriptase,integrase, and nef.
The double-blind, dose-escalation trial will be conducted in 64 healthy, HIV-uninfected individuals, with groups of 12 vaccine recipients and four placebo recipients randomized to four arms. The first group will receive a lower dose of Sev-G(NP), administered intranasally, followed by an intramuscular injection of the Ad35 viral vector vaccine candidate four months later. The second will receive a higher dose of SeV-G(NP) followed by Ad35 four months later. The third will receive the Ad35 candidate followed by SeV-G(NP) four months later, and the fourth will receive two intransal administrations of SeV-G(NP) four months apart.
SeV-G (NP) was developed by the Japanese biotech DNAVEC, while the Ad35 viral vector candidate was developed by IAVI, which is sponsoring the Phase I trial.
In addition to testing the safety and tolerability of the vaccine regimens, the study will evaluate HIV-specific cellular and humoral immune responses in peripheral blood and SeV-specific neutralizing antibodies in all vaccine groups. It will also assess viral shedding in nasal swabs, saliva, urine, and plasma from volunteers to assess the vector’s persistence.
Dagna Laufer, IAVI’s Senior Director for Medical Affairs, said another aim of the trial is to see how well intranasal immunization alone or in a prime-boost regimen with Ad35 induces systemic and mucosal immune responses. As such, researchers will be conducting extensive mucosal sampling to assess HIV-specific Gag antibodies in saliva, transudate (oral fluids that pass through membranes), and nasal, rectal, and vaginal secretions. They will also assay SeV binding antibodies in nasal secretions. The study will further assay such binding antibodies in the serum of all four arms. And among volunteers willing to undergo colo-rectal biopsies, researchers will look for cell-mediated immune responses induced by the vaccine regimen.
Because different vaccination routes elicit different mucosal responses, researchers will look for evidence that nasal immunization stimulates an immune response not only in the respiratory mucosa but in more distant mucosal sites, such as the vagina and gut as well.
Researchers previously evaluated the Sendai as a live, xenotropic vaccine candidate in a Phase I trial for hPIV. That vaccine candidate, which was also administered intranasally, was found to be immunogenic in three of the nine vaccinated volunteers and generally well-tolerated, despite suspected cross-reactive immunity thought to have been induced by previous exposure to hPIV (Vaccine 22, 3182, 2004). But this is the first time Sendai is being used in an AIDS vaccine trial.
One possible obstacle to using SeV vectors could arise from pre-existing immunity to hPIV type 1, which can elicit responses to SeV proteins. As a result, multiple immunizations might be required to achieve a persistent HIV-specific immune response. But an animal study conducted by Chinese researchers suggests another way around this obstacle. While the immunogenicity of SeV, when used alone, is generally not much better than that of a DNA vaccine candidate, the Chinese study found that using a combination of triple heterologous vectors—Sendai, adenovirus, and DNA—encoding gag induced broad and sustained high levels of Gag-specific immune responses in mice and monkeys (Vaccine 26, 6124, 2008).
In a separate study in animals, a prime-boost regimen that used combinations of replication-competent vaccinia LC16m8Δ (m8Δ) and SeV vectors expressing HIV-1 Env efficiently produced both Env-specific CD8+ T cells and anti-Env antibodies, including neutralizing antibodies (PLoS One 7, e51633, 2012).
Which raises the question: Would a SeV candidate be better off containing both Env and Gag inserts? We might soon have an answer: scientists are already developing second-generation SeV candidates encoding proteins more likely to engage both arms of the adaptive immune response.
World Health Organization streamlining HIV guidelines
Ongoing discussions to consolidate and streamline the World Health Organization’s (WHO) hefty and sometimes confusing HIV treatment and prevention guidelines could boost the number of people in low- and middle-income countries eligible for antiretroviral treatment (ART) from 15 million to at least 23 million.
The revised guidelines are likely to recommend that HIV-infected individuals become eligible for ART when they have fewer than 500 CD4+ T cells per microliter of blood. But the WHO is also expected to temper this dramatic shift by suggesting that those with fewer than 350 CD4+ T cells per microliter of blood be given priority.
This expected change is part of a larger effort by the WHO to consolidate all aspects of ART for treatment and prevention for all age groups and populations, according to Gottfried Hirnschall, director of the WHO’s HIV Department. The document should simplify and reduce the number of first-line and second-line drug regimens. It will also seek to provide guidance to countries on how to link people to testing and treatment and retain those being treated in the health care system.
About a year ago, the WHO began recommending that HIV-infected individuals in serodiscordant relationships be offered ART when they have CD4+ T-cell counts under 350. The recommendations stemmed from compelling data obtained from the HPTN052 trial involving 1,763 serodiscordant couples. That study demonstrated that earlier ARV administration can dramatically reduce HIV transmission (see Treatment is Prevention, IAVI Report, Jul.-Aug. 2011). The WHO also issued revised guidelines on the prevention of mother-to-child transmission. But the authors of those guidelines ultimately omitted mention of any review of current data on the preventive benefits of ART in populations other than heterosexual discordant couples.
Now, with evidence suggesting that early treatment improves prognoses and reduces transmission, many advocates and some researchers are calling for the expansion of ART to everyone who is eligible and willing to adhere to prescribed regimens (see Is It Ever Too Early?, IAVI Report, Sep.-Oct. 2012).
Hirnschall said the plan is to release the consolidated guidelines at the upcoming International AIDS Society meeting this summer in Kuala Lumpur, Malaysia.