By David N. Leff
Editor¿s note: Science Scan is a roundup of recently published, biotechnology-relevant research.
Last week, the pharmaceutical industry threw in the towel. Thirty-nine leading pharmaceutical companies dropped their lawsuit seeking to prevent South Africa from making or importing anti-HIV drugs still under their patent protection.
Last year, some 250,000 South Africans died of AIDS ¿ one-tenth of the 2.4 million HIV-positive people throughout sub-Saharan Africa who succumbed to the disease. Ten times as many, 25.3 million, are on HIV¿s death row, infected with the virus.
Acclaiming Big Pharma¿s cave-in, James Love, speaking for an advocacy group that works to push down the price of drugs, crowed, ¿It¿s a huge symbolic victory.¿ But he added, more soberly, ¿It¿s probably much less of a substantive victory than the people realize.¿
A top U.S. bioscientist, Gary Nabel, voiced a similar but somewhat more measured caveat: ¿Among the devastating consequences of AIDS,¿ he wrote in the current issue of Nature, dated April 19, 2001, ¿has been its epidemic spread in the developing world. Because of the considerable expense and logistical difficulty in providing antiviral drugs to populations infected with HIV throughout the world,¿ Nabel added, ¿the biomedical community is looking toward vaccines to help solve this compelling problem.¿
Nabel¿s ¿Insight¿ article appears under the title: ¿Challenges and opportunities for development of an AIDS vaccine.¿ It¿s the last in a series of seven papers that sum up the current status of the AIDS pandemic, and the efforts under way to wrestle it to the ground.
Here are excerpts from Nabel¿s take on the outlook for an effective anti-HIV vaccine:
He begins by comparing the ongoing, still unrewarded, efforts of vaccinologists with ¿the smallpox vaccine, among the most successful interventions in the history of medicine,¿ culminating in its total eradication from the earth in 1977. Two centuries ago, Nabel recalled, the English physician and naturalist Edward Jenner (1749-1823) happened to notice that milkmaids never contracted smallpox, when all around them whole populations were dropping dead from the viral infection. With blood from these unexplained survivors, he prepared and tested the trailblazing vaccine. Immunologists later determined that the smallpox and cowpox viruses cross-reacted, so immunization against the latter protected against the former.
¿Unfortunately,¿ Nabel observed, ¿there are no significant large populations with well-defined resistance to HIV infection, and thus no immune parameters have been identified that correlate with protection.¿ He cited identification of ¿a cohort of exposed seronegative sex workers in Nairobi,¿ which raised hopes that this latter-day surrogate for Jenner¿s milkmaids might provide information about resistance to HIV. Nabel reported, ¿Unfortunately, protection is not always long-lasting, the mechanism of their resistance has not been clearly identified, and thus they have not yielded definitive markers to guide vaccine development.¿
He cited other hurdles:
¿ ¿Lack of immunogens that induce broad and long-lasting immunity;
¿ ¿Unusual and ever-changing genetic diversity of the AIDS virus,¿ whereas ¿a vaccine from a [mere] three strains of poliovirus has been used successfully worldwide;
¿ ¿Limitation of animal models; while nonhuman primates have proved useful, the simian immunodeficiency viruses (SIV) differ significantly from their human counterparts, and chimpanzees seem resistant to the CCR5-tropic primary isolates responsible for infection of most humans.¿
Hence, Nabel recommended, ¿it is evident that human Phase III clinical studies will be needed for the development of effective vaccines. The entire history of human vaccine trials to date,¿ his paper cited, comprises a box score of ¿over 70 Phase I (dose-escalation safety and toxicity), five Phase II (expanded safety and dose optimization) and two Phase III (clinical efficacy) trials, totaling more than 3,500 subjects.
¿Human clinical studies,¿ Nabel concluded, ¿remain the critical link between laboratory research and an effective vaccine.¿
Clued In By DNA Methylation, Hybridon Makes Synthetic Agents To Boost Immune Responses
When a bacterium infects a mammal, it alerts a molecule called the toll-like receptor. This signals the mammalian immune system how to tell bacterial DNA apart from that of the host organism. The difference is in their respective methylation patterns of two nucleotides, cytosine (C) and guanine (G), in their DNA.
¿What this is really pointing us to,¿ said molecular biologist Sudhir Agrawal, vice president of discovery and CSO of Hybridon Inc. in Cambridge, Mass., ¿is how nature has evolved in recognizing C and G when they come too close to each other.¿ Agrawal is senior author of a paper dated March 21, 2001, in the April issue of the journal Bioorganic and Medicinal Chemistry. Its title: ¿Effect of chemical modifications of cytosine and guanine in a CpG motif of oligonucleotides: Structure-immunostimulatory activity relationships.¿
¿If the C and the G come too close to each other,¿ Agrawal told BioWorld Today, ¿they trigger an immune response. The reason is that bacterial DNA is not methylated, but mammalian DNA is. And when a DNA that is not methylated is injected into a human,¿ he went on, ¿then it activates the immune system, just as if the bacteria was infecting it.
¿This is the first research paper,¿ Agrawal observed, that identifies the points of contact within a nucleotide¿s DNA, and how such bases, when modified, can be incorporated into a DNA to activate the immune system.¿
What he and his co-authors did was look for each functionality of the cytosine and the guanine, and fix on certain points of contact that they could change without losing the recognition and immunostimulatory activity.
¿The goal behind this work,¿ Agrawal pointed out, ¿is to create compounds that are much more potent immunostimulatory agents, but that are synthetic. We aim to use them as adjuvants to vaccines, as monotherapeutics to boost the immune system, and as antivirals and antibacterials ¿ for example, in treating asthmas and allergies.¿