Archive for September 14th, 2011

HIV Vaccines From Bangkok – 1

14 September, 2011

Given that I am presently at the HIV Vaccine 2011 Conference here in Bangkok, I thought (belatedly) that I might blog on the proceedings, given Dorian McIlroy’s previous excellent example on CROI in recent months.

Reclining Buddha, Bangkok

Yesterday morning a Crown Princess of the Kingdom of Thailand was opening the first proper session of the oral proceedings: I was not there, as I needed breakfast after handling an email overload and didn’t feel like wearing a suit, so I missed an important performance by a Thai orchestra. Close call, that…!

We were there on Monday night, though, when a lineup of dignitaries presented in an opening plenary session.  First up was Pratap Singhasivanon, the Conference chair from Thailand. He introduced for the ignorant the long history and impressive list of Thailand’s achievements in the world of HIV vaccinology and prevention. It was sobering to hear that 40% of injecting drug users and 33% of men who have sex with men (MSM) were HIV+, despite that history.

Josè Esparza, acting head of the HIV Vaccine Enterprise, came next.  He was of the opinion that this is the Golden Age of HIV vaccines – an age of unprecedented successes and great promise, and that an HIV vaccine to end the pandemic is within reach. He told us that UNAIDS says that behaviour modification and testing is bringing down infection rates worldwide, which is another encouraging development. He thought that we Need increased and sustained financial support for the vaccine effort, however, including for a greater number of trials with short timelines so as to better test a wide range of possible vaccines.

Stanley Plotkin of Univ Pennsylvania is a luminary of the vaccine world, having helped as an industry insider to develop rubella and pentavalent rotavirus vaccines, among others: his job was to tell us how the success of other vaccines could inform the development of HIV vaccines. He said he had thought of saying “There are no lessons!” and sitting back down, but on reflection he had better not.

What he did share was that he thought that antibody response is king, but that it must be functional. A second lesson was that Ab at mucosal surfaces can give sterilising immunity. As an example, injected inactivated poliovirus vaccine (IPV) does not prevent shedding virus in gut while the live oral OPV does as it is much better at eliciting mucosal imm – but interestingly, at the pharynx both work.  A lesson from human papillomavirus vaccination was that while low Ab concentration did not prevent binding of the virus to the first receptor, it did prevent binding to the second – so entry of the virus into susceptible cells was prevented. Another lesson from polio was that high challenge dose can overwhelm immunity, and that IPV was a lot less good at protecting against high challenge doses. It was important that one could still get protection from disease in the presence of infection: for example, Rotateq rotavirus vaccine prevents disease very well, but vaccinees often get infected.

Ab- and cell-mediated immunity can also synergise: with smallpox it was found that both B and T cells are necessary for survival from vaccination, but on secondary exposure to infection in vaccinees, only Ab was necessary to prevent infection.

An important lesson for HIV was that several diseases required vaccine boosters in later life to maintain protection: with diphtheria, immunity in vaccinees declined dramatically while in those naturally infected it did not. Pertussis too needed boosters in children, and several more in ones lifetime to maintain functional immunity.

It was also important to revaccinate where pathogens changed significantly through time and with place – eg rotavirus was much more varied in Africa than elsewhere, as is HIV-1, and strains changed with time in one place, as do HIV and influenza viruses.

An important societal lesson was that vaccination of adolescents and high risk groups may not be accepted: Eg HPV vaccine coverage in the USA in adolescents was only 27% for all 3 doses, despite a very intensive campaign promoting the vaccine. HBV vaccination in high risk adults was also only at 50% and incidence only decreased when adolescents were vaccinated.

Herd immunity was also essential for public health success: eg pneumococcal vaccination of children protected old people indirectly as they were no longer exposed to the live pathogen in familial or sociatal settings.

His conclusions for HIV vaccines were that:

  • one needed a protective Ab response;
  • that IgA or IgG at mucosal surfaces may prevent transmission;
  • strong cellular responses will help control viral replication;
  • there is a good chance that we will get herd immunity;
  • the vaccine composition may have to change envelope component with time and or region;
  • regular boosters will probably be necessary;
  • public health may require universal vaccination of adolescents rather than only of high risk groups.

Sanjay Gurunathan of Sanofi Pasteur gave an industry view of how to move forward from the partially successful Thai RV144 vaccine trial, also reported here in Viroblogy. He observed that the traditional vaccine development model has large volume purchase in developed countries as the main driver, with industry doing R and D and clinical trials and the public sector doing purchase and delivery, with a trickle down to developing countries over time. He thought that HIV needs novel technology, and needs parallel development for 1st and developing worlds – with partnerships being of paramount importance together with guaranteed volume and price to some extent.

He noted that we must realise that for HIV vaccines failure will preceed success in an iterative process, that successes may be population-specific, that we may need multicomponent regimens, that we need to address developing country infrastructure – and that no company, NGO or even country can do it alone.

In this vein, he described a new partnership which was extending RV144 – this was P5, or the Poxvirus Protein Public Private Partnership, of the US NIAID, Gates Foundation, the HIV vaccine Trials Network, the US Military, Sanofi Pasteur and Novartis. This had in mind a broad poxvirus based protein boost regimen to further exploit the surprising success of the regimen in RV 144.

An important result from RV144 was that it was most efficacious at 12 months (60% efficacy) but that protection had dropped >30% by two years, indicating that boosting may significantly and positively impact level and durability of protection.

P5 want to increase efficacy to at least 50%, which would give a big impact for regional epidemics. There is historical precedent for this with cholera and meningococcal vaccines, neither of which is very good but which do impact public health. Their strategy will use a common regimen of poxvirus prime and a recombinant HIV gp120 boost, and will test MSM in Thailand and heterosexuals in South Africa. They planned to use MF59 or similar adjuvant to increase immune responses, unlike the earlier trial. Another new development was that they planned parallel development and clinical tracks, with a research arm in S Africa on NYVAC vaccinia plus protein and adjuvant and a DNA-poxvirus-protein combination.

An interesting evening – with promises of a major announcement to come the following day….