1. HIV Vaccines: The Basics
May 2018

2. Presentation Overview
What is a vaccine?
How would an HIV vaccine work?
Where are we in the search?
What is needed now?

3. What is a Vaccine?
A substance that teaches the body how to recognize and protect itself against a disease-causing agent, e.g. a virus or bacterium
No effective HIV vaccine available today
HIV vaccines cannot cause HIV
Most licensed vaccines against other diseases are 70–99% effective

4. Why a Vaccine Cannot Cause HIV
The whole virus – killed or weakened – is not used in experimental HIV vaccines
Vaccine components resemble the virus and cause immune responses, but they are NOT the actual virus
Only safe, synthetic pieces of the HIV virus are used in vaccine research
In making HIV vaccines, pieces of the virus are copied; the whole virus, or parts of the actual virus, are not being used, which is one of the reasons we can confidently say that the vaccines cannot cause infection with HIV. Many different parts of the HIV virus are currently being explored to form a vaccine (including some of the key proteins that make up the envelope of the virus, DNA fragments and more).

5. Why the Interest in Vaccines?
Vaccines that protect people from getting infected are powerful and effective tools to control and even eradicate diseases. As the graphic shows measles and polio are examples of two epidemics that were successfully controlled by vaccines.
In 1980 there were 4 million measles cases. Due to widespread global vaccination with the measles vaccine (standalone or in combination with rubella and mumps vaccine), cases of measles have dropped substantially to less than 200,000 in 2016.
Similarly the polio epidemic has been successfully controlled because of the development of a polio vaccine and global vaccination efforts, which began in Cases of polio have been dramatically reduced from 400,000 in 1980 to 37 in

6. Vaccine Research in History
It can take a long time to develop a vaccine, even after we know the cause of a disease. While this long time-frame is especially frustrating with HIV, because so many lives are being lost, we are actually on par with the timelines seen for other diseases. There are no vaccines for any other retroviruses, which is the classification of HIV, meaning that it is made up of RNA rather than DNA.

7. Vaccines are Essential
To end the epidemic, an HIV vaccine is needed
Proven prevention options have slowed HIV’s spread – but thousands of people continue to get infected daily
There is a need for a range of HIV prevention methods; there is no silver bullet
Vaccines are one of the world’s most effective public health tools
Cost-effective - single or several doses can provide protection for years
While the ultimate goal of vaccine development is further while other interventions are rolling out, research must continue, and we must advocate now for research to continue in order to ensure sustained decline in infections and an end to the epidemic.
Oral PrEP, male and female condoms, behavior change counseling, male circumcision, needle exchange, and harm reduction, have slowed HIV’s spread but thousands of people continue to get infected daily.
Many of today’s HIV prevention methods require daily use or regular adherence. A vaccine that would require several shots to provide long-lasting protection would be easier to deliver than many current HIV prevention strategies, and when used in combination with other proven options, could help end the epidemic.
Effective vaccines against diseases have helped to slash rates of many illnesses; smallpox vaccine has eliminated the disease completely
Traditionally very cost-effective compared to treatment. Only administered once but we won’t know actual cost until we have one.

8. Types of HIV Vaccines Preventive vaccines
Designed for people who are NOT infected with HIV
If effective, would reduce risk of infection
May also reduce viral load set point after infection
Therapeutic vaccines
Designed for people who ARE living with HIV
If effective, would train the body’s immune system to help control HIV in the body
Most research focuses on preventive HIV vaccines to lower the risk of infection for people who are not infected with HIV.
Preventive vaccines: Used for decades around the world (eliminated small pox, soon polio) and very safe when manufactured and used properly
The viral load set point is the amount of virus (measured by HIV RNA) that the body settles at within a few weeks to months after infection with HIV. Immediately after infection, HIV multiplies rapidly and a person’s viral load is typically very high. After a few weeks to months, this rapid replication of HIV declines and the person's viral load drops to its set point.
Therapeutic vaccines are relatively newer; they are being explored for various diseases, including HIV and certain cancers. The first therapeutic cancer vaccine was licensed by the US Food and Drug Administration in 2010.

9. How Do Preventive Vaccines Work?
By teaching the body to recognize and fight a pathogen
Vaccine carries something that ‘looks and feels’ like the pathogen
The body reacts by activating the immune system and creating antibodies or killer cells and a memory response
Upon exposure to the actual pathogen, antibodies and killer cells are waiting to respond and attack
NOTE: Description is NOT specific to HIV vaccines, but a general definition.
Pathogen: general term for any disease-causing agent, e.g. virus, bacteria, parasite
When you are vaccinated, a small amount of the virus or a copy of the virus is introduced into your blood in a weakened, killed or simulated version. Your body reacts by creating the right antibodies or killer cells (parts of your immune system responsible for recognizing and targeting the pathogen). Your body is now primed to fight this virus because these antibodies and killer cells stay in your bloodstream. As a result, if you were to be exposed to the real virus, the antibodies and killer cells would there already, waiting to attack it.
Note: This is general definition, not specific to HIV vaccines

10. How Might an HIV Vaccine Work?
A preventive vaccine would teach the body to recognize and fight HIV, should it be exposed
Vaccine would carry a component that ‘looks and feels’ like HIV, but is not HIV and cannot cause HIV infection
Vaccine components are copied pieces of the virus known to generate an immune response
Body would react by creating antibodies and/or killer cells and a memory response
Upon exposure to HIV, antibodies and killer cells would be waiting to prevent and/or control infection
When you are vaccinated, a small piece of the virus or a copy of the virus is introduced into your blood in a weakened, killed or simulated version. In making HIV vaccines, pieces of the virus are copied; the whole virus is not being used, which is one of the reasons we can confidently say that HIV vaccines cannot cause infection. Many different parts of the HIV virus are currently being explored to form a vaccine (including some of the key proteins that make up the envelope, DNA fragments and more).
Your body reacts by creating the right antibodies or killer cells. These stay in your bloodstream. As a result, if you were to be exposed to the real virus, the antibodies and killer cells would there already, waiting to attack it.

11. Immune Responses
Preventive HIV vaccines are designed to elicit two arms of the immune system – humoral and cellular
(1) Humoral immunity
Primary action of humoral arm is creating antibodies: Y-shaped proteins produced by B cells in response to a pathogen to prevent infection
Antibodies have multiple functions: attaching to and helping destroy pathogens, keeping the pathogens from entering host cells (neutralization), and calling other cells into action (sensitization).
Antibody
HIV virus
Preventive vaccines seek to stimulate one or two parts of the immune system.
The first line is the humoral. The part of your acquired immune system that creates antibodies (mainly B cells). These are proteins shaped to attach to a specific parts of invaders like HIV. They lock on to the outside of the pathogen/invader and coat it, making it inactive and marking it so other immune cells can come and kill it. Antibodies also prevent the virus from entering the host cells, preventing infection altogether (neutralization); and also calls other cells into action to help block and/or limit the activity of pathogens.
How does this relate to HIV?
Our immune system has a hard time fighting off HIV because the virus can change its outer layer to avoid recognition of antibodies.
B cell

12. Immune Responses
Preventive HIV vaccines are designed to elicit two arms of the immune system – humoral and cellular
(2) Cellular immunity
Two types of T cells: Cytotoxic T lymphocytes (CTL) and T-helper cells
T cells recognize HIV-infected cells, coordinate the immune response (helper cells) and kill the infected cells (CTLs)
Cellular immunity, coordinated by T-cells (cytotoxic, or killer T cells, and helper T cells) seeks out already infected cells to kill them, helping to control the foreign invader that has already taken hold in the body’s cells. Helper T cells coordinate the immune response and prompt other parts of the immune system to act. Cytotoxic T lymphocytes (CTLs) kill infected cells. Because the HIV virus needs to be inside human cells to make more copies of itself, killing these infected cells helps to control the replication of the virus. Vaccines using this part of the immune system are referred to as “T-cell based”.
How does this relate to HIV?
T cells recognize HIV infected cells. T cells are also the targets of HIV, so they become infected themselves. HIV hijacks the very immune cells used to fight the virus.
HIV virus
B cells

13. Preventing vs. Controlling Infection
HIV
PREVENT ESTABLISHED INFECTION?
*****
Vaccine
Administered
A. Lower Initial Peak of Viremia A
B. Lower Set Point B
C. Stop Progression C
HAART
Solid line – viral load in natural HIV infection
Dotted line – potential changes due to vaccination
The solid black line in the middle shows viral load (the amount of virus in blood) in a typical HIV infection: it peaks after infection, then drops back to a set point, and over time it rises again as HIV destroys the immune system.
The dotted line depicts several possible outcomes when vaccinated person is exposed to HIV.
(A) If the antibody response is not effective to block infection with vaccination, and infection occurs, the vaccine could also prompt a T-cell response. The effect of the T-cell response would be to slow down infection by controlling viral load and lowering peak viral load.
(B) A virus could also slow down infection by lowering the viral load set point (the level of your virus in your blood, after the period of primary infection is over and viral load stabilizes). There is probably a direct relationship between lower set point and delayed progression.
(C) The expectation is also that once someone is infected they will begin ART, so the upper dotted line is an indication of taking ART alone. The lower dotted line, shows the effect of a vaccine in combination with antiretroviral therapy in some way, which could perhaps result in lower viral load and thus delayed disease progression over time.
Courtesy of HIV Vaccine Trials Network

14. How Are Vaccines Typically Made?
Live attenuated vaccines (examples: Sabin polio vaccine, measles, mumps, and rubella)
Whole killed virus vaccines (example: influenza, rabies and Salk polio vaccine)
NOTE: This slide discusses general vaccine development, NOT HIV vaccine development.
When someone gets a vaccine, you don’t want to give the person the actual pathogen. This would just make the person sick. So you have to do something creative. Vaccines are dead or inactivated organisms or purified products derived from them.
Live attenuated vaccine: composed of a live pathogen (disease-causing agent) weakened so it’s unable to cause disease. Examples: measles, mumps, rubella
Whole killed vaccine means “killed” or disabled in some way ( “pickled”) – usually heat or chemicals: a vaccine composed of a killed pathogen, unable to cause disease. Examples: influenza and rabies
These are the two types of vaccines that most people are familiar with. However, these two methods are NOT used for the development of HIV; we’re using new genetic technology that does not require using whole (killed or attenuated) HIV virus.
Note: This is general vaccine development, not specific to HIV vaccines.
Courtesy of HIV Vaccine Trials Network

15. Developing an HIV Vaccine is Difficult
Numerous modes of transmission
HIV kills the very immune cells the body uses to defend against disease
HIV makes many copies of itself and mutates, making itself unrecognizable to the immune system
Mutation leads to different subtypes of the virus throughout the world
Nobody has ever eliminated HIV with their own immune system
The virus is extremely effective at evading the immune system because it can mutate (change its out layer)  within an individual, meaning that HIV can learn how to avoid  the effects of a vaccine.
Mutation leads to different subtypes of the virus throughout the world. Each subtype reacts differently to different vaccine candidates, hence testing in many countries is necessary
Our bodies are not able to mount an effective immune response and clear HIV. When making an HIV vaccine, this means scientists are in uncharted territory. They must develop a vaccine that stimulates a stronger immune response than what the body can do on its own.

16. How Are HIV Vaccines Made?
Examples of recombinant vaccines:
DNA vaccines
Vector vaccines (viral and bacterial)
Subunit vaccines
Do not contain HIV – only synthetic copies of fragments of HIV that will create an immune response but cannot cause HIV infection
As an HIV vaccine cannot include a killed or weakened virus (due to possible reactivation), HIV vaccine research requires new technology.
Recombinant vaccines are made up of genetically engineered components of HIV in differing combinations but don’t come directly from HIV. Scientists make synthetic copies of the genes in the lab and use the copies in the vaccine. This is the only type of vaccine being developed for HIV/AIDS. It completely eliminates the chance of getting HIV from the vaccine.
DNA vaccines use copies of single or multiple genes from the HIV pathogen; genes produce particular proteins, causing the immune system to develop a response
Vector vaccines: Same strategy as DNA vaccines, adding a “vector” for better delivery. A vector is a bacteria or virus used to hold genes from another organism, for example canary pox, adenovirus
Subunit vaccines: Presents an antigen to the immune system without introducing viral particles, whole or otherwise. One method of production involves isolation of a specific protein from a virus and administering this by itself.

17. HIV Vaccine Efficacy Results to Date
YEAR
TRIAL NAME/ PRODUCT/CLADE
LOCATION #
RESULT
2003
VAX003
AIDSVAX B/B
Canada, Netherlands, Puerto Rico, US
5,417
No effect
VAX004
AIDSVAX B/E
Thailand
2,546
2007
STEP
MRK-Ad5 B
Australia, Brazil, Canada, Dominican Republic, Haiti, Jamaica, Peru, Puerto Rico, US
3,000
Immunizations halted early for futility; subsequent data analysis found potential for increased risk of HIV infection among Ad5-seropositive, uncircumcised men.
Phambili
South Africa
801
Immunizations halted based on STEP trial result.
2009
Thai Prime-Boost/RV 144
ALVAC-HIV (vCP1521) and AIDSVAX B/E
16,402
Modest efficacy (31.2%)
2013
HVTN 505
DNA and Ad5 A/B/C US
2,500
Immunizations halted early for futility; vaccine regimen did not prevent HIV infection nor reduce viral load among vaccine recipients who became infected with HIV; follow-up continues.
To date, over 200 trials have been performed using a variety of components and methods. Of those only 5 regimens have progressed to phase IIb or III (later stage) trials
Until recently, results from most of the large efficacy trials have been disappointing—the 2 lead candidates (AIDSVAX and Merck Ad-5) did not prevent HIV infection, and results from the Merck STEP trial in 2007 suggest that the vaccine may even enhance HIV acquisition. Remember, human clinical trials are adding to the body of knowledge that we need to eventually design and implement a safe and effective preventive vaccine.
AIDSVAX: the experimental AIDS vaccine made from an component of the HIV envelope (specifically, a sugary protein called gp120) by VaxGen.
ALVAC: a vaccine that combined synthetic fragments of HIV with a harmless form of a bird virus, canary pox.
The RV-144 follow-up study, HVTN 702, began in late 2016 in South Africa. HVTN 702 is a large phase IIb/III trial using a modified RV144 regimen, for the type of HIV most common in sub-Saharan Africa – Clade C– and will enroll 5400 participants. A second phase IIb/III trial of using a different strategy, a mosaic candidate, may start later in 2017 and is expected to enroll 2600 women across sub-Saharan Africa. Slide #20 describes mosaic based vaccines in greater detail.

18. Efficacy Trials Pipeline
Available to download at

19. Pox-Protein Strategies
In 2009 a trial in Thailand (‘RV144’) showed that a vaccine can reduce HIV risk
Moderately effective – 31% protection
Not good enough to license – what’s next?
The Pox-Protein Public Private Partnership (P5) formed to determine and implement next steps
Next steps include:
Several small-scale clinical trials in southern Africa, started January 2015 and ongoing
A large-scale trial (HVTN 702, or the Uhambo Study) launched in October 2016, using a similar regimen to RV144, but made for South Africa; the trial is ongoing
Trial known as the Thai prime boost vaccine trial, which showed, for the first time, that the risk of HIV infection can be reduced by a vaccine. This was the largest HIV vaccine trial to date with over 16,000 trial participants. Evaluated the efficacy of a vax regimen containing two candidates known as ALVAC (canary pox vector) and AIDSVAX (manufactured HIV protein-GP120)—together the vaccine regimen was to stimulate an antibody response along with a cellular response. The vaccine regimen reduced HIV risk by about 31%--a modest reduction but did not affect viral load set point in those who went on to become infected. This doesn’t mean a vax will be licensed soon and available in clinic but the evidence that it was protective is unprecedented.
HVTN 702, a phase III efficacy trial, is testing a modified RV144 regimen, redesigned for the type of HIV that is most prevalent in Southern Africa, known as subtype “clade C”. This modified regimen was first tested in a smaller trial called HVTN 100. In May 2016, the US National Institutes of Health (NIH) announced that HVTN 100 had met its “go” criteria to move forward with a large-scale clinical efficacy trial—HVTN 702—which started in October Positive efficacy results could lead to licensure of this vaccine regimen.

20. Mosaic Vaccine Strategies
A mosaic vaccine is designed to help the body recognize many clades or strains of HIV  
Several mosaic candidates have been developed
Phase I/II clinical trials are ongoing
HPX2008/HVTN 705 (The Imbokodo Study): Phase IIb proof of concept efficacy trial testing a mosaic candidate, delivered using an adenovirus type 26 vector, began in November 2017
Mosaic vaccines were devised by scientists as a way to deal with the challenge of the constantly mutating HIV virus. A mosaic vaccine contains material from different clades of the HIV virus, to help the body recognize and hopefully produce a strong immune response against all clades of HIV– likely a key necessity in a global vaccine.
A phase IIb efficacy trial, HPX2008/HVTN 705, may be launched by late 2017/early 2018 and will test a prime boost regimen of a mosaic candidate. The prime part involves adenovirus vector type 26 (Ad26) that will deliver mosaic components developed by Janssen and partners. The boost consists of gp140 proteins from HIV’s outer layer (or envelope).

21. Antibody Research
Direct transfer of antibodies (passive immunization) being tested for prevention, treatment, and as part of cure
Multiple bNAbs tested in early clinical trials:
Many show safety, tolerability, viral reduction among HIV-positive participants
First proof-of-concept studies of bNAb VRC01 for prevention, the AMP studies, initiated in 2016: &
Researchers identifying and developing more powerful antibodies, and easier ways of delivering them
Early phase studies are also testing combination bNAb approaches
In addition to informing vaccine design, scientists are also studying whether direct transfer (through intravenous drip) of bNAbs could provide protection to HIV-uninfected individuals and help infected individuals control the virus. This strategy is called passive immunization.
As of 2017, two large-scale, proof of concept studies (the Antibody Mediated Prevention studies) are testing the safety and efficacy of direct infusions (intravenous drips) of the bNAB VRCO1 in men and transgender people who have sex with men in sites across Brazil, Peru, Switzerland and the US; and in women in sites across sub-Saharan Africa. Results of this study will help inform antibody research, and help guide vaccine design.
Other ’next generation’ antibodies are currently being developed to be able to last longer in the body, to work against a wide range of HIV strains, and be administered via different routes (including subcutaneously). Some of these bNABs, including a variant of VRCO1 (VRCO1LS) are moving to early phase studies.

22. Antibody Research
Numerous broadly neutralizing antibodies (bNAbs) discovered since 2009
Five main targets of bNAbs on the virus envelope
Studies have shown bNAbs can neutralize many different types of HIV
bNAb research may provide insights into vaccine development and/or could be the basis for a prevention strategy on its own
Research into broadly neutralizing antibodies (bNAbs), that are able to block the activity of many different types of the HIV virus has shown much potential.
Scientists have mapped the shape and structure of these bNAbs and identified the points of contact (binding sites, shown in the graphic) between the antibody and the virus. Understanding the shape of the binding sites for bNAbs is thought to be key to developing a preventive vaccine. An effective immune response will generate bNAbs that can bind to those sites.
bNAbs are being studied as part of a prevention strategy on their own. As of 2017, two phase IIb studies, the Antibody Mediated Prevention studies, are testing the bNAb VRC01 for proof-of-concept that this strategy will be effective for HIV prevention.
The graphic shows key sites on the HIV viral envelope, and the important bNAbs that that bind to those sites to neutralize the virus. The graphic also identified the bNAbs that are currently being studied in human clinical trials.

23. A growing number of more potent and combinations of antibodies are moving into phase I and II clinical trials for testing as passive immunization through various routes, including subcutaneous and intravenous.

24. Advocates’ Checklist
Emphasize that sustained control and the eventual end of the HIV epidemic will depend on methods that provide long-lasting protection, including a vaccine
Promote continued investment to sustain momentum in HIV vaccine research
Ensure vaccine trials are well-conducted, conform to Good Participatory Practices, and react quickly to the changing realities of the HIV response
Demand that stakeholders have a role in planning with researchers for outcomes and next steps from ongoing vaccine trials
Support global partnerships to ensure researchers work together to manage the pipeline of vaccine and antibody candidates
The momentum in the field shows an HIV vaccine is possible and an important part of such a comprehensive, integrated and sustained strategy.
Promote the public-private partnerships and international collaborations that are pushing the field towards realizing the ultimate goal of a HVI vaccine.

25. Key Resources AVAC: www.avac.org/vaccines
Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID)
At Duke:
At Scripps:
Collaboration for AIDS Vaccine Discovery:
European AIDS Vaccine Initiative (EAVI 2020):
European HIV Vaccine Alliance (EHVA):
Global HIV Vaccine Enterprise:
HIV Px R&D Database (PxRD):
HIV Vaccines & Microbicides Resource Tracking Working Group:
HIV Vaccine Trials Network (HVTN):
International AIDS Vaccine Initiative (IAVI):
NIAID:
NIH Vaccine Research Center (VRC):
Pox-Protein Public-Private Partnership (P5):
US Military HIV Research Program (MHRP):
Vaccine Advocacy Resource Group (VARG):

26. Connect with AVAC
Questions, comments and requests for materials should be sent to
Information about HIV prevention generally at and vaccines specifically at
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