ENTERPRISE PRIMERS

IN FOCUS: HIV VACCINE AND PASSIVE IMMUNISATION EFFICACY STUDIES

Introduction

The search for an HIV vaccine has often been described as “a marathon not a sprint”, but it actually looks more like a relay race made up of a series of sprints. Between each sprint, or clinical trial, there have been long rests to redesign the baton before it can be passed on. Each trial completed, however, has brought us a step closer to a safe and globally effective vaccine.

For the first time in many years, there are multiple final-stage HIV vaccine and similar prevention studies underway, evaluating very different approaches and raising the chances of success. Built on many decades of experience, the results of these global trials will emerge over the next two to three years, giving renewed hope to the field.

What are efficacy studies?

Efficacy studies, also known as Phase 3 trials, are the final step in a lengthy process by which vaccines and drugs are determined to be both safe and effective. Phase 3 trials are legally required before new products and vaccines can be licensed for public use.

In the case of vaccines, these studies involve thousands of volunteers in an environment where the virus or bacteria is sufficiently present in the population in order to establish how effective the vaccine is. This also ensures that any unforeseen side-effects do not outweigh the benefit that the vaccine should provide. Some studies achieve the numbers needed by running the trial in many locations around the world. Others have focused on countries like South Africa, which has one of the highest rates of HIV prevalence worldwide.

Trial phases

Because vaccines are usually given to healthy people, there are strict standards to which vaccine development must adhere and higher thresholds for measuring safety. Before a vaccine is allowed to be tested in humans, it has to show potential for triggering an immune response; this is done in pre-clinical testing in animals. Human (clinical) testing then proceeds in three stages to ensure that the vaccine is safe and effective:

Phase 1

Phase 1 is a safety study that involves giving the vaccine to a small group of people (around 100) to ensure that there is no harm and to see if it provokes an immune response.

Phase 2

Phase 2 is a larger safety study with hundreds of people to learn more about safety in diverse populations and the most appropriate dosage.

Due to the high cost of Phase 3 trials, vaccines can be studied in a Phase 2b trial in order to see more quickly if there is any efficacy before committing to a much larger Phase 3 study.

Phase 3

Phase 3 is a final study whereby the vaccine is compared against a placebo to measure how effective it is at preventing infection. These studies enrol thousands of people and can detect rarer side-effects. Phase 3 trials are randomized and double-blinded: neither the researchers nor the participant knows if a participant receives the vaccine or placebo. If found to be safe and effective, the vaccine can be marketed.

Efficacy studies

Currently, five HIV vaccine and passive transfer efficacy studies are underway to evaluate how effective different candidate regimens are against HIV. Three of the studies are using exploring combinations of traditional vaccine approaches, using elements that have shown promising results in earlier clinical studies. Others are looking at completely new strategies.

Some of these vaccines are being studied in men and women separately, and some are comparing the vaccine against other HIV prevention options.

The specific locations and populations for the trials are selected because of their high HIV risks despite existing treatment and prevention programmes. Over 12,700 people in Africa, Europe, Latin America and the US are currently enrolled as volunteers in these trials[1].

[1] ClinicalTrials.gov

Imbokodo and Mosaico

Imbokodo and Mosaico are sister studies testing similar vaccines using a “prime-boost” approach designed to protect against all HIV strains (clades). In these trials, the prime is a viral vector carrying synthetic versions of HIV genes and the boost is a synthetic HIV protein.

Mosaico (HVTN 706) is a four-year Phase 3 trial in 3,800 men and transgender people who have sex with men in eight countries across Europe, North America and South America.

Imbokodo (HVTN 705) is a five-year Phase 2b study in 2,637 women in five countries in sub-Saharan Africa.

The vaccines being evaluated in Imbokodo and Mosaico use the following components that have shown promise in earlier studies:

Ad26 is a viral vector based on a type of human adenovirus, a mild virus that causes the common cold. This vector is a genetically modified, weakened version of the virus so it cannot cause illness. Ad26 is used to carry synthetic versions of three HIV genes that are found in HIV strains circulating in several regions around the world.

Clade C gp140 is a synthetic HIV protein specific to Clade C, the version of HIV that is most common in southern Africa and India.

Imbokodo and Mosaico use slightly different versions of “mosaic” vaccines that incorporate genetic material from a wide variety of HIV clades. Imbokodo participants receive Ad26.Mos4 vector as well as a clade C envelope protein. Mosaico participants receive the same regimen augmented by an additional “mosaic” envelope protein to broaden immune responses.

Janssen Vaccines & Prevention B.V., part of the pharmaceutical company, Johnson & Johnson, sponsor Imbokodo and Mosaico in partnership with the HIV Vaccine Trials Network (HVTN) and the US National Institute of Allergy and Infectious Diseases (NIAID). Earlier clinical studies were also supported by the Bill & Melinda Gates Foundation.

The results of Imbokodo are expected in late 2022, with Mosaico concluding a year later.

The AMP Studies

The Antibody Mediated Prevention (AMP) Studies consist of two parallel studies looking at the efficacy of a broadly neutralizing antibody (bNAb) known as VRC01 in two distinct populations:

HVTN 703/HPTN 081 is evaluating VRC01 in 1,900 women in seven sub-Saharan African countries.
HVTN 704/HPTN 085 is evaluating the same antibody in 2,701 men and transgender people who have sex with men in four countries in North and South America.

The VRC01 antibody is injected directly as an intravenous drip or infusion. This is known as passive immunization: instead of triggering the body into producing its own antibodies, people are given the antibodies directly. The trial will measure how long these antibodies last in people and explore whether a high or low dose is preferable.

The AMP Studies are being carried out by the HVTN and the HIV Prevention Trials Network (HPTN), funded by the NIAID.

The results of the HVTN 703/HPTN 081 study are expected in the last quarter of 2020.

PrEPVacc

PrEPVacc is the first large-scale trial to evaluate the efficacy of HIV vaccines and pre-exposure prophylaxis (PrEP) at the same time. PrEP is a pill taken daily or peri-coitally (before and after sex) by HIV-negative people that reduces the risk of getting HIV. The three-year study in 1,668 men and women in four African countries will compare two DNA vaccines. The first combines DNA with protein-based vaccines and the second combines DNA and MVA with protein-based vaccines. At the same time, the trial will assess a new PrEP drug, Descovy, against the approved PrEP drug, Truvada.

The two vaccines being evaluated in PrEPVacc contain combinations of the following components that have shown promising results in earlier studies:

AIDSVAX B/E is a synthetic protein similar to those found on the outer surface or “envelope” of HIV. As the “boost” component in the RV144 trial, AIDSVAX B/E was part of the only vaccine study to show protection against HIV in humans to date. “B/E” refers to the HIV strains (clades) that it is designed to be effective against. Clade B is the version of HIV that is most common in North America and Europe. Clade E is common in South-East Asia.

CN54gp140 is also a synthetic protein similar to a protein found on the HIV surface.

DNA-HIV-PT123 is a synthetic piece of HIV DNA that instructs the body to make small amounts of proteins that look like the ones found in HIV.

MVA CMDR is a modified viral vector designed to produce responses to three HIV proteins.

PrEPVacc is being carried out by Imperial College London and the London School of Hygiene & Tropical Medicine (LSHTM) Uganda Research Unit, funded by the European Union and several foundations and research institutes. The study is expected to conclude in March 2023.

References

Factsheet series
Key HIV Efficacy Trials in Focus
Clinicaltrials.gov

Glossary

A

Adenovirus: This is a common virus that causes colds and sore throats. A defective adenovirus (one that cannot grow or cause adenovirus infections in humans), such as Ad26, is sometimes used as a viral vector in HIV vaccines.

Antibodies: These are protein molecules produced by the immune system to disable or destroy harmful pathogens (for example, bacteria and viruses).

B

Broadly neutralizing antibodies (bNAbs): These antibodies can protect the body from a wide range of different types of HIV. bNAbs are passively administered candidates in HIV prevention studies; researchers are also exploring how to induce bNAbs with a vaccine.

C

Clade: A clade describes a family or strains or sub-types of HIV descended from the same origin.

D

DNA vaccine (nucleic acid vaccine): This is a direct injection of genetic material that contains the instructions for making specific antigenic protein(s), resulting in direct production of such antigen(s) within the vaccine recipient in order to trigger an active immune response against the antigen (see active immunization).

E

Efficacy: This is a measure of how effective a drug or vaccine is in the context of a clinical trial. Drugs and vaccines can show high efficacy within research studies, but not be very effective in the real world due to issues such as compliance with the vaccine regimen. A vaccine that requires multiple injections to prevent HIV infection may not be as effective if all injections are not received.

H

HIV proteins: The mature, infectious HIV has five structural proteins. Harmless synthetic versions of these are used in many vaccine approaches and tests for infection.

P

Passive immunization: This refers to pre-formed antibodies administered passively to protect against infection. Current formulations are likely to give immediate, but short-lived protection – several weeks to three to four months at most – so needs to be repeated. See also Active immunization.

Phase 1 clinical trial: This is a safety study that involves giving the vaccine to a small group of people (up to 100) to ensure there is no harm and to see if it provokes an immune response.

Phase 2 clinical trial: This is a larger safety study with hundreds of people to learn more about safety in diverse populations, the most appropriate dosage and to expand knowledge of the vaccine’s immunogenicity.

Phase 2b clinical trial: This is a “proof-of-concept” study to see if there is value in taking a candidate further before committing to a much larger and more costly Phase 3 study to establish efficacy. The number of volunteers required is smaller, around 2,000 to 5,000, while more than 10,000 volunteers are required for Phase 3 trials.

Phase 3 clinical trial: This is a final study where the vaccine is compared against a placebo to measure how effective it is at preventing infection (known as efficacy). These studies enrol thousands of people and can detect rarer side-effects, as well as identify the best dosage levels. Phase 3 trials are required before new vaccines can be licensed for use.

Pre-clinical study: This term refers to research undertaken before vaccines can be tested in humans.

PrEP: This acronym stands for pre-exposure prophylaxis. It is a pill or tablet taken daily or peri-coitally (before and after sex) by HIV-negative people that reduces the risk of getting HIV.

Prime boost: This is a combination strategy whereby the immune system is “primed” or triggered by one vaccine component and then a different element targeting another part of the immune system provides a “boost”.

V

Viral vector: This virus does not cause disease in humans and is used as a vehicle to transport vaccine ingredients into the body.

A

Active immunization: This is what takes place when a vaccine stimulates the body to produce an immune response, such as the production of antibodies. Active immune response takes days or weeks to develop but may be long lasting – even lifelong. See also Passive immunization.

Adjuvant: This is an ingredient included with the vaccine to boost the immune response.

Amino acids: These are molecules that link together in combinations to form proteins.

Animal models: Research workers often use laboratory animals as models of humans to test medicinal products they want to develop. The safety of drugs and vaccine candidates are studied in animals at the pre-clinical stage of research. Such testing is a legal requirement before tests on human volunteers can take place in clinical trials.

Antibodies: These are protein molecules produced by the immune system to disable or destroy harmful pathogens (for example, bacteria and viruses).

Antigen: Any substance that causes the body to make an immune response against it is an antigen. Antigens include viruses, bacteria, toxins, chemicals or other substances that usually come from outside the body.

B

C

Clade: A clade describes a family or strains or sub-types of HIV descended from the same origin.

D

E

Envelope protein trimer (gp140): This protein on the surface of HIV binds to immune system cells to gain entry into them, allowing HIV to multiply and spread. The envelope is made up of identical units linked together in groups of three; hence the name, trimer. HIV’s high rate of mutation allows it to change the structure of the trimer and enables evasion by the immune system. Antibodies that target HIV recognize structures (epitopes) on the HIV trimer, while trimer-binding neutralizing antibodies block HIV from infecting cells. Trimers have been engineered synthetically and are now being tested as vaccine candidates that induce active immunity.

Epitope: An epitope is the part of an antigen that is recognized by and binds to components of the immune system, such as antibodies or immune system cells.

F

First in human: This term is used to describe the first time a vaccine or drug has been given to humans.

Follow-up: This describes the monitoring of a person’s health over time after the intervention has been administered. It includes keeping track of the health of people who participate in a clinical study or clinical trial for a period of time, both during the study and after the interventions are completed.

Formulation: This is the way different components are combined to make a vaccine or medicine.

H

HIV proteins: The mature, infectious HIV has five structural proteins. Harmless synthetic versions of these are used in many vaccine approaches and tests for infection.

M

Monoclonal antibodies (mAbs): These antibodies are produced by identical immune cells that are all clones of a unique parent cell. Broadly neutralizing antibodies (bnAbs) are mAbs that bind diverse and neutralize multiple HIV strains, despite their differences.

P

Pathogen: A pathogen is an organism (for example, a bacteria or virus) that has the potential to cause disease.