HIV Vaccine Development Dr. Patricia Fast HIV Vaccine Development Dr. Patricia Fast (MD, PhD) Senior Technical Advisor, International AIDS Vaccine Initiative Adjunct Clinical Associate Professor, Infectious Disease, Pediatrics Stanford University School of Medicine How It Began 1984 • Human Immunodeficiency Virus (HIV-1) discovered as the cause of AIDS • Prediction: a vaccine will soon be developed! Non-Human Primate Models Focusing on this dominant model • Simian Immunodeficiency Virus (SIV) lead to a bias – SIV Mac 239 causes AIDS-like disease in Macaques almost impossible to neutralize • SHIV hybrid (with HIV Envelope) allows research into neutralizing antibodies in macaques • Chimpanzees can be infected by HIV, but seldom get AIDS False starts • Traditional vaccine approaches fail in NHP model . Killed SIV does not really protect against SIV o Initial positive result was an artifact . Live attenuated SIV protects, but is not safe o Attenuated vaccine was shown to regain virulence The screen versions of these slides have full details of copyright and acknowledgements 1 HIV Vaccine Development Dr. Patricia Fast How would an AIDS vaccine work? A note about virus biology • HIV has many mechanisms to escape immune recognition e.g. : . Rapid formation of variation . Structural aspects How would an AIDS vaccine work? Immune Mechanisms • T cells . Kill virus-infected cells . Slow down or stop replication of viruses within cells . Can directly kill virus infected cells . Secrete substances that block viral replication Can neutralize virus when they prevent entry; by binding viral envelope protein or the cellular receptors HIV is extremely variable Europe and North America East Africa Southern Africa, India and China Part of an HIV phylogenetic tree The screen versions of these slides have full details of copyright and acknowledgements 2 HIV Vaccine Development Dr. Patricia Fast An AIDS vaccine will be tough HIV is extremely variable HIV targets CD4 cells . No sense in making a vaccine against . Making recovery difficult or impossible epitope that will not be encountered HIV disguises itself HIV integrates into cell genome . Variable portions act as immune decoys . Some cells persist for life-creating . Envelope protein structure is complex hidden ‘reservoirs’ and changes on attachment . Reservoirs are established early . Envelope protein is ‘decorated’ in infection with carbohydrates that cover up some key targets . Any vaccine immune-response must block infection or work quickly . Molecular mimicry - Some portions to control it of HIV resemble self antigens . Many potential neutralizing antibodies - not produced because of self tolerance Newer methods of making candidate AIDS Vaccines Chimeric Viruses RNA can also be used Chimeric viruses Non-Replicating Replicating Chimera Chimera Virus Virus . Likely to give a stronger and longer lasting immune response: o Against vector + HIV part in vaccine . Is the new virus safe? . Examples: Tested replication competent chimeric HIV vaccines o Based on smallpox vaccine • In some non-human primates vaccine o Sendai virus completely controlled or eliminated infection o Adenovirus • Works even in presence of preexisting CMV o Modified CMV SIV vaccine • Important: most humans are infected with CMV from a young age • Mechanism: unique class of effector CD8+ cells? The screen versions of these slides have full details of copyright and acknowledgements 3 HIV Vaccine Development Dr. Patricia Fast Two goals 1) How to make a vaccine that gives the right type of immune response? . Strong antibody response can prevent infection . Strong T cell response can eradicate infected cells 2) How to make broad enough responses? . Some people will not be exposed to a broad range of virus and others will The ideal, a universal AIDS vaccine HIV vaccine development history . Relevancy of clade specific vaccines – is it enough? o The clades are not isolated to specific areas of the world o There is variation within clades – T cells or antibodies will not necessarily recognize all the viruses from the vaccination clade nor fail to recognize viruses from other clades Goal: Induce immune responses that cross over all the different clades The ideal, a universal AIDS vaccine (T cell responses) 2) Conserved sequences . Focuses on parts of the sequences that do not 9 amino acid change between the viruses peptide epitope . Some conserved sequences do not change as they are critical for proper function . Conserved epitopes are likely to be in any HIV encountered . Variants in epitope that escape immune detection are unlikely to function well T cell 12 The screen versions of these slides have full details of copyright and acknowledgements 4 HIV Vaccine Development Dr. Patricia Fast The ideal, a universal AIDS vaccine (antibody responses) • ~5% of healthy HIV+ persons have, after 3 years, broadly neutralizing antibodies • Some are neutralizing for over 90% of HIV types • These antibodies serve as a guide for vaccine development • Over time the antibodies evolve and increase in epitope affinity and efficacy • These changes take time – not helpful to the person already infected • A vaccine that mimics the antibody evolution - feasible/realistic? How to know if an AIDS vaccine is beneficial in humans Randomized placebo controlled trial Make sure the group understand Identify population at risk the trial, benefits and trust the staff Randomly assign into the groups Vaccine group Neither the staff nor the Placebo group participant know which group they are in Regular follow-up and counseling Statistically significant decrease in vaccine group = efficacy Trial end points and targets Selection of end points and targets is critical to demonstrating vaccine efficacy The main focus has been infection incidence rather In the trialthan looking viral titers both and at clinical infection disease prevention and viral load control • Anti-retrovirals should be given as soon as possible • Measuring viral titers may be important → people are not always diagnosed as soon as they become infected . Immune system is damaged and viral reservoirs are created in this time . The virus is being transmitted in this time The screen versions of these slides have full details of copyright and acknowledgements 5 HIV Vaccine Development Dr. Patricia Fast Populations at risk for HIV infection • For a successful trial: . Find at risk individuals and educate them . Provide health and prevention strategies . Account for risk reduction by trial size expansion o ARV given to HIV+ people can prevent transmission o ARV given to uninfected people can prevent infection o However, there are problems with taking these drugs Efficacy trials of AIDS vaccines Phase IIb or III trials Antigen Delivery Population Years4 Result Trial Name Envelope (gp120) Protein with alum Injection Drug Users 1990-2003 No effect Vax 003 protein adjuvant MSM, 1999-2003 No Effect Vax 004 N America, Caribbean, Australia Gag, Pol, Nef (genes) Adenovirus type 5 MSM, N America 2005-2007 (Subset1 had higher Step infection rate At-risk men and Jan-Sept 2007 Stopped early, no Phambili women effect 2 South Africa Env, Gag, Pol, Nef DNA followed by MSM 2009-2011 No effect HVTN505 genes Adenovirus type 5 (Subset excluded1) Env, Gag, Pol genes ALVAC (canarypox) General population 2003-2009 31% protection3 RV144 env, gag, pol, nef in 2 provinces Envelope (gp120) plus protein with of Thailand protein alum adjuvant5 LOW RISK! 1. Subset was uncircumcised men and/or those with antibodies to adenovirus 5 before vaccination 2. In followup after unblinding late increase in infection if vaccinated 3. Suggestion of higher protection rate at 1 year that waned (not statistically significant) 4. In several trials, longer-term follow-up occurred after unblinding 5. Same protein used in Vax003 • 6 trials like this have been done with four regimens: . 2 were single vaccine . 2 were prime – boost combination The first HIV vaccine trials Antigen Delivery Population Years Result Trial Name Envelope Protein with Injection Drug 1990-2003 No effect Vax 003 (gp120) alum adjuvant Users protein MSM, 1999-2003 No effect Vax 004 N America, Caribbean, Australia • Vax 004 primarily in North America combined envelope proteins from two local HIV isolates which were clade B • Vax 003 in Thailand combined US/European clade B envelope and one clade E envelope from Thailand The screen versions of these slides have full details of copyright and acknowledgements 6 HIV Vaccine Development Dr. Patricia Fast The Step and Phambili trials Antigen Delivery Population Years Result Trial Name gag, pol, nef Adenovirus type 5 Men who have 2005-2007 (Subset1 had higher Step (genes) Sex with Men infection rate) (MSM), High risk hetero women, N America At-risk men Jan-Sept Stopped early, Phambili and women 2007 no effect2 South Africa Why was an increase in susceptibility seen? . Effect of adenovirus 5 on T cells previously exposed to vector? The HVTN505 trial Antigen Delivery Population Years Result Trial Name env, gag, pol, DNA followed MSM 2009-2011 No effect HVTN505 nef genes by Adenovirus (Subset type 5 excluded1) • 3 doses of DNA vaccine followed by replication incompetent Adenovirus 5 vector • These vaccines included env and the internal components • Designed to induce both T cell and antibody responses 1. Those with antibodies to adenovirus 5 before vaccination were removed The RV144 trial Antigen Delivery Population Years Result Trial Name env, gag, pol ALVAC (canarypox) General 2003-2009 31% protection3 RV144 genes env, gag, pol, nef population