News yesterday that Bionor Pharma’s HIV vaccine Vacc-4x managed to significantly reduce the viral loads of HIV positive patients is the first bit of good news for a long while in a field that has been littered by numerous pipeline failures and largely forgotten by big pharma companies, despite what is a desperate need for an effective treatment (Bionor’s comeback story continues with positive HIV data, February 15, 2012). But those very failures mean that while the news is encouraging there still could be a very long way to go before Bionor or any other company can claim success in finding a cure.
The difficulty in coming up with a vaccine for HIV has meant that there are very few late stage candidates in development and no approved vaccines in the Western world (see table). Flush with a significant uplift in its share price Bionor is already talking about conducting further studies and finding a partner for the phase IIb drug. The history of HIV vaccines, however, might mean attracting a big name to give credibility to the programme will prove difficult.
When the HIV virus was first classified in 1984, there were pronouncements from both governments and pharma companies that a vaccine would be available within five years. Almost thirty years on, the prospect of cracking what has become one of the holy grails of drug development seems as remote as ever.
In recent years one of the factors hindering efforts in the vaccine approach is the fact that in the West HIV has become a chronic and to a large extent manageable disease, meaning that the need for a vaccine has shifted to the developing world where the payers would be cash strapped national governments or international health organisations.
This is not an attractive value proposition for big pharma who would have to carry out trials among thousands of patients for approval (Therapeutic focus – Novel HIV approaches continue to suffer lack of interest, July 19, 2010).
Big companies are also still nursing several failures in the field. One of the most high profile disappointments was Merck calling time on its 3,000 person phase IIb Step Study of prophylactic vaccine V520 in 2007. Development was stopped after it was found that of the HIV negative trial enrolees who were at high risk of contracting the disease there were near identical infection rates between people who had and had not been vaccinated. Also those who had received the vaccine and became infected did not have reduced viral loads, indicating the vaccine had had no effect.
Tough nut to crack
There are a number of factors that people believe make the virus difficult to develop an effective vaccine for including the fact that unlike other vaccines that use natural immunity gained from recovering from an illness to prevent re-infection there are few if any confirmed patients who have recovered from HIV.
HIV is also the infection not the disease and most vaccines are designed to tackle the disease, in this case Aids.
But the biggest hurdle to vaccine development has been the constant shifting and mutation of the virus, because the regions on the surface of antigens capable of eliciting an immune response are more variable than those in other viruses. The mutability of the virus also means that the virus in an infected person can evolve over time to help it evade both antibody mediated and T cell mediated immune responses.
Vaccine development is also not helped by the fact that individual viruses are very variable, meaning that the immune response created by a vaccine needs to be very broad to account for the variety in viruses, rendering narrow band vaccines ineffective.
What’s on offer
Currently the only marketed HIV vaccine is Immunitor’s V-1 Immunitor, but as the Thai company is private little is known about the sales or effectiveness of the oral vaccine that aims to be a treatment for HIV.
As with other vaccines HIV research is split into therapeutic and prophylactic use; the two other most advanced vaccines, Sanofi’s Alvac-HIV and Roche’s AidsVax/gp120, are both prophylactic vaccines in phase III.
But research on the two has stalled since the ambiguous outcome of a 16,000 patient study in Thailand of the two drugs used in combination. Alvac-HIV, a canarypox virus with three HIV genes grafted onto it, was used as the prime vaccine and AidsVax, originated by Genentech, was used a booster.
Using the drugs in combination was supposed to work by one vaccine creating antibodies and the other alerting white blood cells to attack and kill the virus. Initially it appeared that the drug had shown some benefit in preventing high risk individuals from contracting the virus, but subsequent analyses showed there was little or no benefit. Sanofi has since invited public-private partnerships to continue development of Alvac-HIV.
|Late stage HIV vaccine pipeline|
|Product||Company||Indication Level 3|
|Marketed||V-1 Immunitor||Immunitor||HIV treatment|
|Phase III||AIDSVAX/gp120||Roche||HIV prophylaxis|
|Phase II||Global HIV Vaccine||GenVec||HIV prophylaxis|
|HIV DNA Vaccine||Vical||HIV prophylaxis/treatment|
|HIV Vaccine||GlaxoSmithKline||HIV treatment|
|MVA-BN HIV Multiantigen||Bavarian Nordic||HIV prophylaxis|
|DNA/MVA Vaccine||GeoVax Labs||HIV prophylaxis|
|VIR201||Virax Holdings||HIV treatment|
|Vacc-4x||Bionor Pharma||HIV prophylaxis/treatment|
|FIT-06||FIT Biotech||HIV treatment|
|DNA/MVA Vaccine||Emory University/GeoVax Labs||HIV prophylaxis/treatment|
Further down the line
Of the drugs in phase two development the majority of the space is dominated by smaller players such as Bionor and Bavarian Nordic. While GlaxoSmithKline is listed as having two vaccines in development, there have been no clinical updates on the programmes since 2010.
Alongside Vacc-4x, Bionor has its prophylactic treatment Vacc-C5, which the group has yet to run in humans. One of the plans for the jab is to combine it with Vacc-4x in an attempt to get a vaccine that both reduces viral load and prevents the movement of patients into full Aids.
Bavarian Nordic has placed its MVA-BN HIv Multiantigen, which encodes eight genes from HIV, on clinical hold stating that it will not initiate any “cost-intensive” studies and all future development will depend on external funding.
Virax Holdings is hoping to get round this funding issue through the formation of a non-profit organisation in South Africa, where is its conducting phase I/IIa trials. The group has managed to get some funding from mining companies and governments across the world to conduct its ongoing trial.
Shocking new approaches
Although not included in the table there are some interesting and novel approaches being taken in phase I, in particular electroporation (EP). This is the application of short impulses of electric current at the site of intramuscular vaccination to hopefully increase the immunogenicity of HIV vaccines.
The method temporarily disrupts the cell membrane, allowing the DNA to pass into the cell. Inovio Pharmaceuticals, one of the group’s looking at this technique, has its own proprietary EP delivery system that it is using in conjunction with proprietary vaccines Pennvax-G and Pennvax-B HIV vaccines. So far studies have shown a higher T cell response rate compared with therapy without EP.
Ichor Medical Systems is also using EP with its ADVAX-EP vaccine and has out-licensed the technology to Profectus BioSciences, which is using the delivery device to test its pDNA vaccine. In non-human primate studies the immunogenicity of the vaccine was increased significantly with the use of EP.
Not to be sniffed at
The induction of mucosal antibodies is being investigated by Mymetics and partner Pevion Biotech. With the aim of preventing HIV attachment to epithelial cells on mucosal surfaces such as the genital and rectal tracts the therapy could provide a first line defence against infection. In a phase I trial of intramuscular and intranasal administration of MYM-V10 the vaccine was safe, well tolerated and produced a strong immunogenicity in serum and mucosal sites. Mymetics is currently preparing a combined phase I/II study.
What this looks at the space shows is that while there maybe several promising earlier stage candidates in the pipeline, the real trick with HIV vaccines will not only be getting them to later stages, but also reigniting the interest of the larger players who are the only ones with the might to conduct the large scale trials needed in this space.