By Regina McEnery
Trial Evaluating DNA/Ad35 Prime-boost Regimen Commences in Africa
A Phase I trial that began in December will evaluate the safety, tolerability, and immunogenicity of a DNA-based HIV vaccine candidate with or without co-administered recombinant interleukin (IL)-12 delivered via electroporation in a prime-boost regimen with a recombinant adenovirus (Ad) serotype 35 vector-based candidate delivered by intramuscular injection.
The randomized, double-blind, placebo-controlled trial known as B004 will enroll 75 healthy HIV-uninfected men and women ages 18-50. Vaccinations are underway in Rwanda and Uganda. A third clinical research center in Kenya will also enroll volunteers once the trial receives regulatory approval.
Both the DNA vaccine candidate, known as HIV-MAG, and the adjuvant, known as GENEVAX IL-12, were developed by Profectus BioSciences. The Ad35-GRIN/ENV candidate was designed by IAVI, which is also the sponsor of the trial. By using Ad35, a rare serotype of adenovirus, researchers are hoping to circumvent the issue of pre-existing immunity to the viral vector; however, a recent study suggests this may not be entirely straightforward (see Adenovirus Vectors: Promise and Possible Pitfalls).
Investigators are evaluating five different heterologous prime-boost regimens in the B004 trial. Four of the five groups will receive the DNA vaccine candidate first (in three of the groups the DNA will be co-administered with IL-12 and in the other group no IL-12 will be given) followed by the Ad35 boost. The other arm will receive the candidates in reverse order. Two different doses of IL-12 will be evaluated, as well as two different dosing schedules of the prime and boost (for details, go to clinicaltrials.gov).
Both the DNA and IL-12 will be administered intramuscularly via an electroporation device developed by Ichor Medical Systems that is meant to enhance immune responses. The small hand-held electroporation device uses a needle to inject the vaccine and four thin wires to administer electrical pulses that are milliseconds in length. This device was previously tested in a Phase I trial, sponsored by Rockefeller University, of a DNA candidate known as ADVAX involving 40 HIV-uninfected adults in the US. The study found that the candidate and delivery method were safe and well tolerated, and the magnitude of immune responses, as measured by interferon (IFN)-γ ELISPOT, were up to 70-fold higher in volunteers who received the DNA candidate via electroporation as compared to vaccinees who received the vaccine candidate via standard intramuscular injection (1). The same device is also being used in a Phase I therapeutic vaccine trial involving 60 HIV-infected adults. The trial, which is ongoing, is comparing volunteers who receive the DNA vaccine intramuscularly via electroporation to those who receive it through standard intramuscular injection.
1. PLoS One 6, e19252, 2011
Trial Testing Mucosal and Systemic Delivery of DNA Vaccine Candidate Begins
A Phase I trial launched in December will examine three different routes of vaccination of a DNA-based candidate containing trimeric gp140 from a clade C virus, the dominant strain circulating in southern and East Africa, administered in combination with two experimental adjuvants.
The trial, known as MUCOVAC2, is funded by the Wellcome Trust and is being conducted at two clinical research centers in the UK. Twenty women will receive either a high or low dose of the DNA candidate administered via intramuscular injection, along with glucopyranosyl lipid adjuvant (GLA), which was developed by the Seattle-based non-profit Infectious Disease Research Institute (IDRI), a product-development partnership that is part of a vaccine consortium—including St. George’s, Imperial College, Hull York Medical School, and the Medical Research Council Clinical Trials Unit—that developed the vaccine candidate.
GLA is a synthetic glycolipid based on monophosphoryl lipid A, a lipid form of detoxified lipopolysaccharides (LPS), a component of the outer membrane of gram-negative bacteria, which is used as an adjuvant in licensed vaccines. Scientists have found that GLA induces antibody and cellular immune responses and speculate that it works by activating toll-like receptor 4, which senses bacterial LPS (see A Vaccine’s Little Helper, IAVI Report, May-June 2011 and An Immunological Rationale for Vaccines, IAVI Report, Nov.-Dec. 2010).
An additional arm of the trial includes six women who will receive the DNA vaccine candidate delivered nasally in the form of drops, along with the adjuvant chitosan, a compound derived from the outer skeleton of shellfish and insects that is thought to improve the immunogenicity of vaccines administered mucosally. Chitosan is not used in any licensed vaccines as this time but is used as a dietary supplement.
An additional 10 women will receive the DNA vaccine candidate both systemically and mucosally. This group will receive an intramuscular injection of the vaccine candidate and GLA, followed by vaginal application of nine doses of a microbicide gel, each containing 100 micrograms of the gp140 protein. Vaginal application of the DNA gp140 vaccine candidate was previously tested in a Phase I trial involving 22 healthy women ages 18-45 from the UK. The study found the candidate to be safe, though it did not induce local or systemic immune responses (1). In pre-clinical studies, the gp140 recombinant protein has been shown to be immunogenic when administered systemically in mice and intravaginally in rabbits.
“This is the first time the [candidate] is being used intra-nasally or intramuscularly,” says Catherine Cosgrove, honorary consultant in infectious disease and general medicine at St. George’s, University of London, who is leading the study. Cosgrove says the intramuscular injection combined with vaginal application aims to induce a more focused mucosal stimulation of the immune system.
1. PLoS One 6, e25165, 2011
Polio Eradication: One Step Forward, One Step Back
A multi-decade effort to rid the world of polio took a major step forward in February after the World Health Organization (WHO) announced that it was removing India from a list of countries where the disease is still endemic. However, there has been an alarming surge in new cases in neighboring Pakistan and Afghanistan (see table, below).
India reached this crucial milestone because of a US$2 billion campaign that the south Asian country largely self-financed. During national immunization days throughout India’s 35 states and union territories, public health workers vaccinated more than 170 million children under age five annually—70 million of them multiple times. They then followed up with seven smaller immunization days aimed at hard-to-reach populations. On Jan. 13, 2012 the country had gone a year without a single new case of wild poliovirus infection. The last case of wild poliovirus was reported in the West Bengal region of India on Jan. 13, 2011.
Three years ago, India led the world with polio cases (741), but signs the country was turning the corner became evident the following year when transmission of the most dangerous strain of wild poliovirus and the cause of 95% of India’s polio cases until 2006, dropped to record low levels, led by the absence of cases in Uttar Pradesh. If three years elapse with no new polio cases, India will be declared polio-free.
“India’s success is arguably its greatest public health achievement and has provided a global opportunity to push for the end of polio,” according to a statement by Margaret Chan, the director-general of the WHO, a collaborator in the Geneva-based Global Polio Eradication Initiative that was launched in 1988.
The Global Polio Eradication Initiative is a public-private partnership led by national governments and spearheaded by the WHO, Rotary International, the US Centers for Disease Control and Prevention, and the United Nations Children’s Fund. The Initiative has spent $8.2 billion so far toward establishing a polio-free world, focusing on 200 countries, and immunizing 2.5 billion children over 23 years.
India’s struggle against polio has been focused largely on the states of Uttar Pradesh and Bihar in northern India, where high population density and poor sanitation have complicated efforts to break the transmission cycle. The trivalent oral polio vaccine, which contains weakened versions of three types of wild poliovirus, has had a lower efficacy (74%) in these northern regions compared to the remainder of India (85%), possibly because substandard living conditions make children more prone to diarrheal diseases that can prevent the vaccine from working effectively. Additionally, the strains in the trivalent vaccine can interfere with each other, producing immunity to one strain but not another.
The success in India was heralded by the Bill & Melinda Gates Foundation, which has made polio eradication its top priority. The Foundation has committed close to $1.4 billion to polio eradication efforts. “The challenge in India was mind-boggling,” remarked Bill Gates in his annual letter describing the Foundation’s priorities for the coming year. “It’s hard to imagine how you would design a polio campaign that reached every Indian childÉBut the government kept raising awareness and improving the quality of its campaigns, even in the toughest locations.”
Oliver Rosenbauer, a spokesman for the Global Polio Eradication Initiative, says while the news from India is encouraging, the increase in polio cases in Pakistan, Nigeria, and Afghanistan is of grave concern. “There is very real recognition that things need to be scaled up rapidly and concretely, in particular in the remaining endemic areas,” he says.
Also worrisome are Angola, Chad, and the Democratic Republic of Congo, where the circulation of imported viruses has persisted for more than 12 months, and a handful of countries in Africa and Asia, including China, which have been grappling with outbreaks triggered by imported cases.
Last month, the WHO’s executive board declared the completion of its polio eradication efforts a programmatic emergency for public health, and urged the handful of countries where polio still exists to declare a national public health emergency. The WHO board also called for certification-standard surveillances to identify the emergence of circulating vaccine-derived polioviruses, and adequate funding to interrupt wild poliovirus transmission globally, which they believe can be achieved by the end of 2013.