UK-CAB.9 May 2004
United Kingdom
Community Advisory Board
(UK –CAB)
31 May 2004
Report on 9th Meeting
Contents
Members attending 2
1. Introduction - Aims of day 3
2.Introduction to immune system - Henry Graeme-Smith 3
-Different cells in the immune system 3
-Approaches to vaccine development 5
- Community involvement in UK-based clinical research
on HIV vaccines, microbicides and other new
prevention technologies – Julian Meldrum 6
4. Introduction to IAVI and UK trials – Maite Suarez 7
5. Thorny issues in vaccine research – Saul Walker10
6. Pre-exposure prophylaxis - Gus Cairns11
7. Feedback from microbicides conference - Jo Robinson12
8. Overview of pipeline microbicides – Julian Meldrum16
- AOB and programme for next CAB
Presentations are all available to download from the website for the May 2004 meeting:
Members attending
Kirsi AholaLambeth PCT
Willys AkokoAfrica Advocacy Foundation
Gus CairnsPositive Nation
Polly ClaydenHIV i-Base
Simon CollinsHIV i-Base
David CourthreadNational AIDS Trust
Ben CromartyNorth Yorkshire AIDS Action
Jenni FredrikssonAvert
Cathal GallangerLiving Well Programme
Henry Graeme-SmithHIV trainer
Richard JacksonTHT West
Mohamde JowataBrent and Harrow PCT
Ben Hills-JonesAvert
Francis KahembweWaverley Care Solas
Martin LeighUK Africa HIV Alliance
Badru MaleBrent and Harrow PCT
Julian MeldrumNAT
Rachel NkamaUganda AIDS foundation
Jonjo OlubunmiWest African Networking
Jo RobinsonTHT London
Kapula SimoneWaverley Care Solas
Maite SuarezIAVI, Amsterdam
Saul WalkerIAVI, UK
Brian WestWaverley Care Solas
Emma Positive Place
Report by Simon Collins, HIV i-Base
1.Introduction to the meeting
Everyone was welcomed to the 9th UK-CAB meeting which was organised with support of IAVI and NAT to focus on vaccine and microbicide research.
The meeting was planned to include training on the immune system and how vaccines work and to have an overview of the current state of vaccine research.
The recent microbicides conference in London was attended by over 1000 delegates, included several CAB members and the meeting included feedback from those members that attended.
Finally, we hoped that the overlapping interest in both areas of research might be an interesting area for a specialist sub-group to develop, in association with existing community networks in the UK and internationally.
2. Introduction to immune system
Henry Graeme-Smith
As background for the vaccine and microbicide presentations Henry Graeme-Smith provided an overview on the immune system (see also slides).
Different cells in the immune system
The first section briefly introduced different types of cell:
Phagocytes – macrophages
B-cells
CD8-cells
CD4-cells
Antigen-presenting cells
The simplest immune response that humans have (also insects) is the cell-based response – where cells recognise a foreign organism or bacteria, move towards it and engulf what ever it comes across. Phagocyte means ‘eat-cell’ – and macrophages work in this way.
Humans also use B-cells that recognise specific antigens. Antigens are parts of foreign material.
Before a B-cell comes into contact with a new antigen for the first time it is called a naïve B cell. The B-cell has to learn what to recognise but once they have done this they clone ‘daughters cells’ that produce antibodies that in turn can neutralise viral attachment to other cells. A B-cell that has come into contact with antigen – and is then coded for that specific antigen – is called a memory B-cell.
The antibodies also signal to phagocytes.
With new infections not previously seen by the immune system – naïve B-cells need time to generate response and fight infection. Naïve cells divide into two clones – memory cells that live for years waiting to be triggered and plasma cells that release large amounts of the appropriate antibody.
Memory B-cells (to infections that the body has already encountered – perhaps years earlier) mean the body can respond more quickly if it encounters the same infection in the future.
Vaccines try to create this response and trigger the immune system to have a memory.
Phagocytes and B-cells only work when virus is outside of cells.
When a virus or bacteria is inside a cell the immune system uses lymphocytes called T cells (ie CD4 and CD8 cells). CD stands for ‘cluster of differentiation’ and relates to the cells on the surface of the CD cell that helps it recognise antigen (but you rarely need to know this!).
CD8 cells are ‘cytotoxic’ (ie toxic to cells).These are also called NK or Natural Killer cells. They are the ‘sharks of the immune system’.
CD8 cells recognise infected cells from markers on the outside of a cell that shows it is infected – and it then destroy infected cells and therefore stop more viral or bacterial production.
Cells that coordinate this process are CD4 cells (also called ‘helper cells’) and they become activated by antigen-presenting cells which engulf an invading organism, break it down and present viral antigen on their surface for immune system to recognise – ie presenting to CD4 cell.
Immunology and cell behaviour is very complicated, and many cells perform different roles in different situations. It is useful to know that some CD4 cells (Th1) provide the bodies humoral immune response and some (Th2) provide the cell-mediated response.
This cell activity (activity, turnover and cell death etc) is only possible because of chemical messengers produced by the immune system. These are called cytokines and include IL-2 (which is being studied as an immune-based therapy).
Two other cells you will see in immunology studies are CD45RA (naïve) and CD45RO (memory) cells.
HIV presents such a problem from a medical perspective, because the cells it uses to destroy infections, are the cells that the virus uses for replication. The more HIV replicates the more the body responds to signals to destroy those immune cells. An immunologist describes untreated HIV infection as a state of heightened immune activation. More T cells are produced and more cell death is activated – eventually leading to a depleted pool of CD4 cells and ‘immunodeficiency’.
At initial point of new viral infection – a period of uncontrolled viral replication – numbers of CD4 cells drop – then as immune system recognises the new infection and produces antibodies at around week 6-8.
Preventative vaccines aim to stop initial viral burst by pre-priming the immune system to previously unseen virus.
Approaches to vaccine development
An ideal target vaccine needs to:
-prevent mucosal infection
-be safe
-require as few injections as possible – ideally single dose administration
-provide long-term protection – ie not require regular boosters
-be cheap
-stable for administration (ie preferably stable at different temperatures, not need refridgeration
-active against broad viral species/subspecies [all M subtypes, N, O]
This would be an ideal vaccine – but the vaccines currently available for other infection often do no have these characteristics – so they are just aims.
From the introduction above, a vaccine could work using different immune responses:
-Humoral response – based on antibodies and B-cells that produce them
-Cell-mediated response – based on CD8 cells
-Mucosal immunity – as above but based in mucosa
-HIV-specific CTL-mediated response (ie and this is the current trend)
Types of vaccine:
- live attenuated (weakened) – ie original smallpox – vaccinia – but vaccination may lead to slow disease (for HIV)
- inactivated (killed) vaccines – ie Salk polio vaccine. Not shown benefit for HIV. Virus is easily broken down – so process of attenuation destroys the necessary viral target
- Recombinant sub-unit envelope vaccines seek to stimulate antibodies to HIV by mimicking proteins on the surface of HIV (e.g. gp120) but initial research was strain-specific and produced poor antibody responses
- Recombinant vectored virus incorporate harmless genetic HIV material into established vaccine (ie ALVAC which had some therapeutic success)
- DNA vaccines – getting genetic sequences of HIV into human cells – therefore cellular immune system then generates protections – immune system produces own antigen
- Combination or prime-boost vaccine – look at combinations of different types of vaccines – where one ‘primes’ the immune system and another ‘boosts’ the immune response once it has been generated.
Q What about approaches to inject vaccines closer to mucosal target – ie groin?
AThis is interesting even though vaccines are not related to local area, but to target the specific response in different areas of the body. Although cells move around the body – they remember where they have come from – to target the immune response back to where it is needed – therefore the hope that injecting in the groin may generate stronger immune response in that area. One difficulty inherent in that cross-species research often relates to body size of mice compared to humans, etc and huge relative quantities required when scaling up to humans – especially DNA vaccine approaches.
Q What about risks from vaccination –ie to children? Live vaccines can transmit virus to non-vaccinated people. ie from stool (faeces) of children to parents from live polio vaccine. Vaccine can then develop into mutated virus over time.
ANational vaccination days attempt to provide blanket protection. When negative reactions have been reported, sometimes this has been because vaccinations were arranged close to times related to other health threats – ie close to malaria season and those deaths have been associated to the vaccines. This is why there is a move away from live vaccines – but live vaccines are also generally more effective.
QWhat about different strains? A Retrovirus study looked at how virus works on different strains…
AEarly antibody work was very strain-specific – not even sub-type specific – V3 loop etc – and consensus is that they are useless in practice because of viral mutation and escape. Antibody research focuses on monoclonal antibodies (produces in cell lines in culture) and tests potential agents on wide panel of viral strains. Focus on macrophages rather than T-cell responses. About 6 antibodies now described.
QWhy do people get the flu after a vaccine?
AOften because the health system chose the wrong strain to vaccinate against when they were producing (and predicting) which vaccine would be most effective that Winter.
3.Community involvement in UK-based clinical research on HIV vaccines, microbicides and other new prevention technologies
Julian Meldrum (
Julian Meldrum then lead a discussion on the role that community organisations could play over vaccine and microbicide issues.
This summary only briefly summaries the issues covered – please see the slide presentation online for more details
Questions for discussion included:
-What kinds of community involvement are possible, desirable or necessary, especially here in the UK?
-When to separate and when to mix vaccines, microbicides, PEP?
-What forums or other organisational structures exist now or should be developed to support UK community involvement?
It also included discussions of similarities and differences of community involvement in treatment-related trials and networks that are often more advanced (phase 2-3 etc) compared to much vaccine and microbicide research that is often at a much earlier stage of development.
UK-CAB members were interested in extending the CABs work on treatment research and access to cover research on HIV prevention technologies.
This is already happening where use of ARVs for prevention (ie tenofovir) is an obvious area, as it builds on the experience of treatment advocates in relation to the use of ARVs for treatment. In fact, the relationship is so close that it might best be integrated with other work on ARVs.
- Microbicide trials are already recruiting HIV positive women for initial safety and acceptability studies. It is obviously appropriate for the UK CAB to be considering the need for training and support to those involved in that process. The use of ARVs as microbicides could further strengthen the case for UK CAB involvement.
- UK-based HIV vaccine research, it is further from direct clinical application than ARV or microbicide prevention research
- There is real value in developing a dialogue between both community organisations and researchers…
Issues in vaccine and microbicide research for a CAB sub-group include:
- Potential therapeutic (or not) use in HIV positive people
- Reviewing protocols and volunteer info, including feedback options during/after trial
- Helping ensure best care and treatment for people that become positive in a trial and the issue of HIV+ test results for people who are not infected (if applicable)
- Media strategy to place trials in broader context and prevent damaging hype
- Developing work with other community groups (in the UK and internationally) and networks involved in this area.
4. Introduction to IAVI
Maite Suárez
Maite Suárez, European Country Programmes Officer with IAVI (International AIDS Vaccine Alliance) then gave an overview of the work of this important organization. IAVI is a non-profit NGO with offices in New York, Amsterdam, Brussels, Nairobi and New Delhi.
IAVI’s mission is to accelerate the development of a safe and effective preventive AIDS vaccine and to ensure that once is available it will be readily accessible, especially to those most in need
The powerpoint slides for this lecture outline the IAVI programme in detail.
An excellent bulletin newsletter in also available online which provides updates on both IAVI-related research and other advances:
Information is available in English and Spanish.
IAVI strategies include:
- to ccelerate research and development of promising candidates through to clinical trials
- to mobilise public support to AIDS vaccines by increasing awareness, information, political lobbying
- to facilitate the involvement of the private sector
- to prepare global access to AIDS vaccines
The organisation develops alliances in the North and South; public and private sectors.
Funding comes from:
-Governments (~ 66%): Canada, The Netherlands, UK, US, Denmark, Sweden, Norway, Ireland
-Multilateral (~ 3%): World Bank
-Private Foundations (~ 30%): Bill & Melinda Gates, Rockefeller, Alfred P. Sloan, Starr
-Private sector (~ 1%): ie Becton, Dickinson and company
IAVI: Expenses 1996-2008
-R&D 77%
-Advocacy work 11%
-Administrative and general costs 8%
-Fundraising 2%
-Political lobbying 2%
Stages of vaccine research
i) Pre-clinical: From biological idea and concept
ii) Laboratory development: Construction of product (using good lab practice)
In parallel manufacturing (GMP); animal testing
iii) Animal testing: Toxicity, immunogenicity, including GLP and GMP identical
Stages of clinical vaccine research
- Phase I, preliminary, n=dozens; low risk of contracting HIV; safety ‘ is it safe?’
then…. Phase II, intermediate: n= hundreds; low and higher risk of contracting HIV; more safety, immunogenecity, dosage, route of administration
if all well then…Phase III, advanced: n= thousands; high risk of contracting HIV infection; efficacy vs. placebo
After 23 years since HIV indentified, there have been only 3 phase-3 trials – with one main target vaccine
Completed Trials UK
Study ID / Sites / Design / # / Dose/Sched. / Status
#001 / Oxford / Single blind / 18 / 2 x
0.1 or 0.5 mg DNA / Complete
#005 / Oxford / Open
Rollover / 9 / Late MVA boost of #001 volunteers / Complete
Ongoing Trials UK
Study ID / Sites / Design / # volunteers(Vac. / Pl) / Dose/Sched. / Status
#006
Prime/Boost / London and Oxford / DB, R, PC
Prime/day 0
EB (8/12w)–LB (20/24w) / 120 / Prime 0.5/2mg DNA; Boost
5x10e7
MVA / Vaccinations
Complete, trial compl. by Aug 04
#010
Prime/Boost / London
(Kenya) / DB, R, PC
Prime (0/1m)
Boost (5/8m)
Route SC, IM, ID / 111
(90/21) / Prime 0.5mg DNA; Boost
5x10e7 MVA / Enrolment complete
#011 / Wales
(SA, CH, NL) / DB, R, PC
MVA
Route SC, IM, ID / 111
(90/21) / MVA dose escalation till 2.5x10e8 / low and mid dose enrolment compl.
#016 / Oxford / DB, R, PC
MVA
DNA/MVA / 24
(16/8) / Day 0,28,56
MVA 1x10e8
DNA 4 mg / 12 volunteers enroled
One study temporarily on-hold while reviewing safety concern – ie previously pre-cancerous cells in mice exposed to different MVA malaria vector in non-associated studies – similar concerns again (in studies O10, O11, O16). This will be clarified.
5. Thorny issues in vaccine research
Saul Walker, IAVI Policy advisor – (based in NAT in London)
Saul Walker then discussed some of the ethical and practical issues raised in vaccine research, that are of particular importance form a community perspective.
- Vaccine positivity (including insurance) – ie negative volunteers testing HIV-positive on HIV test
- How vaccines are developed and researched for certain sub-types and clades (that may not reflect the most affected population that need a vaccine
- Partial efficacy (what protection ratre would be acceptable) and end-points
- Cohort selection
- Phase 2b or not Phase 2b
- Placebo selection
- Standards of Care for trial participants in developing countries
Vaccine positivity
- Vaccines often intended to induce antibodies which mean that volunteers may test HIV+ using standard HIV tests - though it is possible to determine true and vaccine positivity through selective tests, such as PCR. Volunteers provided with information and directions for future testing
-Insurance - ABI recognised issue of vaccine positivity but assumptions that volunteers are ‘high risk’ may still be an issue
Clades
- Genetic variability in HIV produced numerous clades
- Variability challenging for vaccine design but don’t know how important clade issue is: Animal data showing cross reactivity for a number of candidates but only clinical data will be conclusive
- Potential for multi-clade vaccines: VRC has an ABC product – difficulty with stability
- Some parts of virus relatively well conserved – better targets?
- Broad protection a key objective
Efficacy
- Types of Immunity are possible: Sterilising Immunity would protect from infection – best hope but most difficult, seen in some animal models
- Disease mitigation – where you become infected but vaccine delays or prevents of disease progression
- Reduced Infectiveness where a lower viral load leads to reduced transmission
Limited Efficacy
- Some of the people may get protection all of the time OR all of the people may get protection some of the time OR combination of both
- Efficacy and effectiveness results both have the potential for behavioral reversals (ie people stop practising safer sex). Measuring effectively brings its own challenges – ie effect of perceived benefit on prevention efforts