Research updates that headlined this year's Conference on Retroviruses and Opportunistic Infections
The Bill & Melinda Gates Foundation announced a US$10 billion commitment over 10 years to fund research, development, and distribution of vaccines to people in the world’s poorest countries. “We must make this the decade of vaccines,” said Bill Gates, after he announced the substantial donation during the World Economic Forum’s annual meeting in Davos, Switzerland, which took place January 26-31.
The $10 billion pledge is in addition to the $4.5 billion already committed by the Gates Foundation for vaccines. The Foundation said its increase in vaccine funding was inspired by the remarkable progress in recent years in improving access to existing vaccines and the introduction of new vaccines against rotavirus and pneumococcal disease. The World Health Organization estimates that together pneumonia and rotavirus infection account for 1.3 million deaths every year in children under age five, mostly in developing countries.
The Gates Foundation also estimates that an additional 1.1 million children could be saved with the rapid introduction of a malaria vaccine beginning in 2014. A Phase III efficacy trial of GlaxoSmithKline (GSK) Biologicals’ RTS,S malaria vaccine candidate began last year. Depending on the results of this trial, the candidate vaccine could be submitted to the European Medicines Agency for regulatory review by 2011 and be ready for distribution by 2012, according to GSK and the Malaria Vaccine Initiative.
Julian Lob-Levyt, executive secretary of the GAVI Alliance, a Geneva-based non-profit organization that partners with drug companies, health agencies, and charities to provide both financial and programmatic support for vaccination programs in 73 of the poorest countries in the world, noted that the Foundation’s $10 billion pledge set a new precedent in global health. “Vaccines remain the most cost-effective way of saving children’s lives,” he says. —Regina McEnery
A controversial 1998 research paper in The Lancet, a prominent medical journal, which prompted an abrupt decline in childhood immunizations, was recently retracted after a UK panel determined that the authors who conducted the study acted unethically.
The 1998 research paper described an unexpected pattern of intestinal lesions in 10 of 12 children with developmental disorders. The authors of the study said the lesions occurred, in most cases, after the children received the measles-mumps-rubella (MMR) vaccine, which is typically given by 15 months of age. The paper also cited previous, unrelated studies that attempted to link patterns of intestinal lesions and another intestinal disorder, ileal-lymphoid-nodular hyperplasia, with sudden behavioral changes, including autism spectrum disorders in young children.
The study did not prove vaccination against MMR caused intestinal disorders. Yet, Anthony Wakefield, a researcher from the Royal Free Hospital and School of Medicine in London who led the study, held a press conference following publication of the study, at which he urged parents to shun the combination MMR vaccine in favor of having their children vaccinated with the three vaccines individually, with a year interval between each dose.
This study is widely credited with sparking an anti-vaccination movement that resulted in declines in immunizations, particularly in the UK. In 1997, the year before the study was published, 91% of children in the UK were vaccinated. In 2003, the rate had dropped to 60% in some parts of the country.
Ten of the paper’s 13 authors—not including Wakefield—submitted a partial retraction in 2004 saying they felt research into the intestinal lesions should continue, but stressed that the paper established no causal link between the MMR vaccine and autism.
Following the retraction in February, the US Centers for Disease Control and Prevention (CDC) released a statement reminding parents that vaccines are safe, effective, and that they save lives. “The Lancet’s retraction of Dr. Wakefield’s study is significant,” the CDC noted. “It builds on the overwhelming body of research by the world’s leading scientists that concludes there is no link between the MMR vaccine and autism.” —Regina McEnery
What are some of the recent developments that are helping researchers identify new targets for HIV vaccine design?
Vaccines protect against disease by priming the immune system to generate the specific types of immune responses necessary to stop an invading pathogen before it causes harm.
Most vaccines induce different types of immune responses, including B cells. B cells produce antibodies—Y-shaped proteins that can latch on to viruses and inactivate or neutralize them—which are considered critical to the protection afforded by many, if not all, vaccines (see VAX February 2007 Primer on Understanding Neutralizing Antibodies). Antibodies can also help inhibit infection through other mechanisms of action that don’t involve direct neutralization (see VAX January 2010 Primer on Understanding Antibody Functions: Beyond Neutralization).
Many scientists believe that an AIDS vaccine will need to induce antibodies, in addition to other immune responses, to be highly effective at protecting against HIV. And because the circulating strains of HIV are so diverse, antibodies that can neutralize a broad array of HIV variants, so-called broadly neutralizing antibodies (bNAbs), have been a major target for HIV vaccine researchers.
To design vaccine candidates capable of inducing these bNAbs, researchers are using a reverse engineering approach. They start by identifying the antibody or antibodies the vaccine should induce and then try to identify precisely where these antibodies attach to HIV. This site is then used by scientists to design vaccine immunogens—the non-infectious fragments of HIV that are included in vaccine candidates. These immunogens are then tested to see if they can elicit these antibodies in people.
Until recently, only a handful of bNAbs were identified, limiting the number of targets that could be exploited for vaccine design. However, in the past year, researchers have unearthed a fresh crop of new, and in many cases more potent, antibodies. Five of the eight newly discovered antibodies were isolated from individuals infected with the clades of HIV most prevalent in Africa, where the HIV/AIDS burden is greatest and a vaccine is needed most.
Identifying new targets
The search for new bNAbs typically involves screening blood from HIV-infected individuals to see if it can neutralize a panel of laboratory viruses. These viruses are ranked by how easy or difficult they are to neutralize.
If serum, a component of blood, from an HIV-infected individual can neutralize several different viruses in a laboratory test, then researchers isolate the antibodies present in the serum. While HIV-specific antibodies are common in HIV-infected individuals, bNAbs are much rarer.
Two of the recently discovered antibodies—PG9 and PG16—were discovered by IAVI scientists in collaboration with researchers from The Scripps Research Institute in California. After screening blood from 1,800 HIV-infected individuals in Africa, North America, Europe, Asia, and Australia, researchers identified these two potent bNAbs from a single HIV-infected individual in Africa (see VAX October 2009 Spotlight article, Vaccine Research Gains Momentum).
Three other antibodies—HJ16, HGN194, and HK20—were discovered after screening 400 HIV-infected individuals through the Collaboration for HIV Vaccine Discovery (CAVD), in an effort led by a researcher from the Institute for Research in Biomedicine in Switzerland.
The remaining three antibodies, one known as VRC01, were identified by scientists at the Vaccine Research Center (VRC) at the US National Institute of Allergy and Infectious Diseases.
Different laboratory techniques were used to identify these antibodies. For instance, PG9 and PG16 were identified by screening first for neutralization and then for the ability of the antibodies to bind to HIV. This was important because these antibodies bind only weakly to HIV in the form in which it is studied in the laboratory, and had the binding test been conducted first, researchers might not have discovered these antibodies. The VRC01 antibody was found by combining B cells from HIV-infected individuals with virus particles that had been manipulated so that researchers could detect only those antibodies that bind to a specific site on the virus.
Researchers are now focusing on using these antibodies to reverse engineer vaccine candidates, starting with characterizing where on HIV these antibodies bind. Most of them bind to the spike-like protrusions on the surface of HIV, which is called the Envelope protein because it envelopes the virus’ genetic material.
Some of the recently discovered antibodies target different parts of HIV’s Envelope protein, suggesting to researchers that there are a number of ways to neutralize HIV and thereby prevent infection. (see VAX October 2009 Spotlightarticle, Vaccine Research Gains Momentum). PG9 and PG16 target a section of the virus that is more accessible to bNAbs, making it a promising target for vaccine developers. VRC01 and HJ16, as well as one of the older bNAbs known as b12, all bind to HIV at the site where the virus binds to human CD4+ T cells, the preferred target of the virus.
Work is now underway to characterize these sites on the virus and to design immunogens based on them. Although there are still many challenges involved, researchers hope that improved candidates based on these bNAbs will eventually be ready for testing in clinical trials.