Editorial: Proof of Concept
The recent announcement of the Phase II proof-of-concept efficacy trial of Merck’s replication-defective adenovirus vector vaccine candidate, MRK-Ad5, is a very important step for the AIDS vaccine field.
The collaboration between Merck and the HIV Vaccine Trials Network (HVTN) was announced in public discussions at the National Institutes of Health’s AIDS Vaccine Research Working Group (see Vaccine Briefs) and then at the recent AIDS Vaccine 2004 Conference in Lausanne, Switzerland. The trial, scheduled to begin at the end of this year, will test one of the most promising AIDS vaccine candidates in development.
In ongoing Phase I and II trials, MRK-Ad5 has elicited in up to 75% of vaccinees the most robust HIV-specific cellular immune responses yet seen in humans. The new trial will determine if cell-mediated immunity, at least as currently defined, can be effective in either preventing HIV infection or at least reducing post-infection viral load; the latter would hopefully lead to improved prognosis for individuals and lowered transmission rates for populations. Results of the trial are expected to be available in late 2007 or early 2008.
This means the field has three years to prepare for success. Unfortunately, even if MRK-Ad5 proves to be an effective vaccine it will likely not be available for widespread use in humans. Adenovirus is a natural human pathogen that causes a manifestation of the common cold and pre-existing immunity to adenovirus serotype 5 (Ad5), on which the new candidate is based, is widespread in many human populations. In the US and Europe about 35% of the population has significant levels of immunity to Ad5 that appear to render the vaccine candidate ineffective at inducing HIV-specific responses; in many developing country populations that figure rises to more than 80%. A potentially precarious political aside to a successful proof-of-concept trial, therefore, will be to explain to the general public, particularly in developing countries, that an effective AIDS vaccine cannot be distributed widely. Trial sponsors would do well to get the point across early.
So between now and the end of the trial alternative adenoviral vectors need to be identified and evaluated. Pre-existing immunity to other human adenovirus serotypes seems to be far lower and some (like serotypes 11 and 35) are already being tested as vectors. Adenoviruses that naturally infect other species, chimpanzees in particular, are also being developed and assessed for their potential as immunogenic vectors. If several different adenoviral serotypes can be developed they might be used sequentially in prime-boost immunization regimens to increase the strength and durability of HIV-specific cellular responses (see Research Briefs).
These improvements and expansions of the adenoviral vector repertoire must be accompanied by efforts to ensure that the process development and manufacturing scalability potential are optimized, to ensure that once an effective vaccine is identified it can be produced in large quantities for distribution and use where it is needed most in the shortest timeframe.
In the same time period, the perennial problem of eliciting humoral immunity against HIV has to be cracked. Even if adenovirus vectors prove outstandingly effective, adding a broadly effective neutralizing antibody component to the vaccination regimen can only solidify protection.
Of course the field must also prepare for disappointment, and in such a scenario effective humoral immunity may prove even more crucial. As ever, novel vectors should continue to be identified and developed, perhaps ones that induce cellular immunity that is qualitatively different to that which is now induced. Those answers will come from further advances in basic immunology in many different systems, and HIV research must embrace and make partners of scientists in other disciplines. Advances in measuring and consequently understanding mucosal immunity will be important, as will insight into strategies to induce protective innate immunity. Better adjuvants and other innovative delivery strategies that will enhance the magnitude and duration of immune responses to practically useful levels are also needed.
The challenges remain as formidable as ever, so we must prepare for success but be equipped for a setback.
New-look IAVI Report print edition
We hope our readers will appreciate the newly re-designed IAVI Report print edition which reflects our aspiration to become more of a forum for the AIDS vaccine community. In order to engage as many readers as possible and serve the research community, as we move forward we will strive to increase the ‘harder’ scientific content to encompass the latest research and be a forum for analysis and debate of the issues that will ultimately lead us closer to realizing an effective preventive vaccine. We will now publish objective Review articles and more opinionated Perspective pieces from influential scientists and other leaders in the field on topics integral to AIDS vaccine research and associated disciplines.
This won’t come at the expense of accessibility; our aim is to appeal to a diverse range of readers, so that there will be something for all audiences, irrespective of their degree of scientific training. We hope that the more socially-inclined articles will help remind scientists why they are doing what they are doing, and that the more molecular biology- and immunology-oriented pieces will challenge non-scientists to increase their knowledge base.
To illustrate, this issue of IAVI Report focuses on topics related to the transmission of and early events after HIV infection, and features Review and Perspective articles in those areas. Melissa Pope writes about dendritic cell-dependent events immediately after HIV has breached the mucosal barrier; a better understanding of these events will provide insight into what may be a decisive window of opportunity to stamp out potential infection. Robin Shattock writes about the accelerating momentum in microbicide research, the difficulties that come with a growing field, and the parallels with other HIV/AIDS prevention and treatment initiatives.