hiv

• HIV vaccine


  Can be either a preventive vaccine (protect individuals from being infected) or a therapeutic vaccine (treat HIV-infected individuals)
• HIV vaccine approach


  Can be either active vaccination (induce an immune response against HIV) or passive vaccination (consist of preformed antibodies against HIV)
• There is currently no licensed HIV vaccine on the market, but multiple research projects are trying to find an effective vaccine
• Some HIV-infected individuals naturally produce broadly neutralizing antibodies which keep the virus suppressed, and these people remain asymptomatic for decades
• Potential broadly neutralizing antibodies have been cloned in the laboratory (monoclonal antibodies) and are being tested in passive vaccination clinical trials
• One HIV vaccine regimen, RV 144, has been shown to prevent HIV in some individuals in Thailand
• The urgency of the search for a vaccine against HIV stems from the AIDS-related death toll of over 35 million people since 1981
• In 2002, AIDS became the primary cause of death due to an infectious agent in Africa
• HAART (highly active antiretroviral therapy)


  Medication that provides many benefits to HIV-infected individuals, including improved health, increased lifespan, control of viremia, and prevention of transmission to babies and partners
• HAART must be taken lifelong without interruption to be effective, and cannot cure HIV
• Options for the prevention of HIV infection in HIV-uninfected individuals

  • Safer sex (for example condom use)
  • Antiretroviral strategies (pre-exposure prophylaxis and post-exposure prophylaxis)
  • Medical male circumcision
• Vaccination has proved a powerful public health tool in vanquishing other diseases, and an HIV vaccine is generally considered as the most likely, and perhaps the only way by which the HIV pandemic can be halted
• HIV remains a challenging target for a vaccine
• Factors that make HIV vaccine development different from other classic vaccines

  • There are almost no recovered AIDS patients
  • HIV infection may remain latent for long periods before causing AIDS
  • Killed HIV-1 does not retain antigenicity and the use of a live retrovirus vaccine raises safety issues
  • The epitopes of the viral envelope are more variable than those of many other viruses, and are masked by glycosylation, trimerisation and receptor-induced conformational changes
• Reasons for the ineffectiveness of previously developed HIV vaccines

  • HIV is highly mutable, allowing the virus to evade the immune system
  • HIV isolates are highly variable, requiring a vaccine to induce broad immune responses
• The difficulties in stimulating a reliable antibody response has led to the attempts to develop a vaccine that stimulates a response by cytotoxic T-lymphocytes
• Another response to the challenge has been to create a single peptide that contains the least variable components of all the known HIV strains
• Animal model for HIV vaccine research

  • Monkeys can be infected with SIV or the chimeric SHIV
  • The well-proven route of trying to induce neutralizing antibodies by vaccination has stalled because of the great difficulty in stimulating antibodies that neutralise heterologous primary HIV isolates
  • Some vaccines based on the virus envelope have protected chimpanzees or macaques from homologous virus challenge, but in clinical trials, humans who were immunised with similar constructs became infected after later exposure to HIV-1
  • There are some differences between SIV and HIV that may introduce challenges in the use of an animal model
• A new animal model strongly resembling that of HIV in humans, involving generalized immune activation as a direct result of activated CD4+ T cell killing, has been developed in mice
• NIAID-funded SIV research has shown that challenging monkeys with a cytomegalovirus (CMV)-based SIV vaccine results in containment of virus
• Approaches to HIV vaccine development in clinical trials

  • Most initial approaches have focused on the HIV envelope protein
  • Recombinant canarypox vectors have provided interesting results, with increasing the complexity of the vectors increasing the percent of volunteers with detectable CTL responses
  • Other strategies that have progressed to phase I trials include peptides, lipopeptides, DNA, an attenuated Salmonella vector, p24, etc.
• In 2011, researchers in National Biotech Centre in Madrid unveiled data from the Phase I clinical trial of their new vaccine, MVA-B, which induced an immunological response in 92% of the healthy subjects
• In 2016, results were published of the first Phase I human clinical trial of a killed whole-HIV-1 vaccine, SAV001, which demonstrated a good safety profile and elicited antibodies to HIV-1
• Preventive HIV vaccine trials

  • The recombinant Adenovirus-5 HIV vaccine (V520) was tested in two Phase 2b studies, Phambili and STEP, but was stopped after it was associated with an increased risk of HIV infection in some recipients
  • HVTN 505, a Phase IIb study, was launched in 2009 but halted in 2013 due to meeting requirements of futility
  • The global Antibody Mediated Prevention (AMP) trial (HVTN 703 and HVTN 704) is the first phase IIb trial of a monoclonal antibody for HIV prevention
  • The phase IIb trial called HVTN 705/Imbokodo is testing the mosaic vector vaccine Ad26.Mos4.HIV and the aluminum phosphate-adjuvanted Clade C gp140 vaccines
• The results of the trial prompted the reexamination of vaccine development strategies
• HVTN 505, a Phase IIb study, was launched in 2009 but halted in 2013 due to meeting requirements of futility
• Although no further participants were vaccinated, the HVTN 505 study is still in follow-up
• In May 2016, Lawrence Corey and Myron Cohen of the HIV Vaccine Trials Network (HVTN) and HIV Prevention Trials Network (HPTN) respectively partnered to launch the global Antibody Mediated Prevention (AMP) trial (HVTN 703 and HVTN 704), the first phase IIb trial of a monoclonal antibody for HIV prevention
• Monoclonal antibodies (mAbs) are a passive vaccination strategy
• HVTN 703 and HVTN 704 test VRC01, a mAb that targets the CD4 binding site
• In 2017, Janssen and the HVTN launched the phase IIb trial called HVTN 705/Imbokodo, testing the mosaic vector vaccine Ad26.Mos4.HIV and the aluminum phosphate-adjuvanted Clade C gp140 vaccines which are designed to prevent infection of all HIV subtypes around the world
• Biosantech developed a therapeutic vaccine called Tat Oyi, which targets the tat protein of HIV
• Tat Oyi was tested in France in a double-blind Phase I/II trial with 48 HIV-positive patients who had reached viral suppression on Highly Active Antiretroviral Therapy and then stopped antiretrovirals after getting the intradermal Tat Oyi vaccine
• There have been no passive preventive HIV vaccines to reach Phase III yet, but some active preventive HIV vaccine candidates have entered Phase III
• In February 2003, VaxGen announced that their AIDSVAX B/E vaccine was a failure in North America as there was not a statistically significant reduction of HIV infection within the study population
• AIDSVAX B/E was a component, along with ALVAC, of the RV 144 vaccine trial in Thailand that showed partial efficacy in preventing HIV
• The AIDSVAX B/E and ALVAC vaccines targeted the gp120 part of the HIV envelope
• The RV 144 study involved 16,395 participants who did not have HIV infection, 8197 of whom were given treatment consisting of two experimental vaccines targeting HIV types B and E that are prevalent in Thailand, while 8198 were given a placebo
• After three years, the vaccine group had HIV infection rates reduced by about 30% compared with those in the placebo group
• It was discovered that participants receiving vaccines in the RV 144 trial who produced IgG antibodies against the V2 loop of the HIV outer envelope were 43% less likely to become infected than those who did not, while IgA production was associated with a 54% greater risk of infection than those who did not produce the antibodies (but not worse than placebo)