Introduction
This is a unique and exciting moment for HIV vaccine development, characterized by renewed momentum and unprecedented promise. While many teams have temporarily turned their attention in 2020 to finding a COVID-19 vaccine, there has been an acceleration in learning that has pushed the field closer than it has ever been to delivering safe and effective HIV prevention products.
Since it was introduced in the late 1990s, highly active antiretroviral therapy has changed the face of the HIV epidemic and saved many millions of lives. We now know that those taking daily HIV medication as prescribed can stay healthy and can’t pass on HIV. In addition, pre-exposure prophylaxis (PrEP) – where it is available – is proving to be a hugely powerful tool in preventing HIV infection among those most vulnerable to transmission.
Despite these advances, 1.7 million people acquired HIV in 2019 alone. A vaccine that can durably prevent infection is therefore considered to be the most powerful tool against the HIV-1 pandemic and the cornerstone of an integrated approach to prevention. Anthony Fauci, the Director of the US National Institute of Allergy and Infectious Diseases (NIAID), and his colleagues recently said that finding safe, effective and durable vaccines for HIV – as well as for COVID-19 – are top priorities for the NIAID, which is one of the biggest global funders of HIV vaccine development.
An overview of the different approaches to HIV vaccine and passive immunization development and delivery is given in HIV vaccines: An introduction. This briefing focuses on broadly neutralizing antibodies (bNAbs), one of the most exciting new developments in HIV prevention studies. It is part of a series of briefings on new approaches that harness the immune system against HIV.
The antibody response to HIV
Antibodies work by binding to their specific target and either blocking its action or flagging it as “foreign” so other parts of the human immune system can clear the “invaders” away.
The body produces a diverse immune response to HIV infection. One component – the antibody response – starts relatively late in infection with the production of very low levels of non-neutralizing antibodies (nNAbs; also called binding antibodies). Although nNAbs bind to HIV proteins, they have no direct, substantial impact on the infectivity of the virus. However, they are useful in diagnosing infection.
The body next starts producing neutralizing antibodies (NAbs) that target antigens involved in enabling HIV enter cells. While NAbs fully recognize single HIV envelope antigens, another antibody type, called broadly neutralizing antibodies (bNAbs), have potent activity against a
wide range of HIV strains or clades as they recognize structures (called epitopes) that are on the surface of different HIV clades (see Box). The bNAbs being studied in HIV prevention studies target the HIV envelope protein trimer. bNAbs are monoclonal antibodies (mAbs), which means that are produced by identical immune cells that are all clones of a unique parent cell.
Because such potent bNAbs are able to bind to the diverse HIV strains and potentially stimulate other types of immune responses, they are a major focus for HIV prevention studies. Animal studies have already shown that bNAbs introduced before viral infection provide protection against infection.
What are HIV clades?
The main HIV-1 virus group, called Group M, has dominated the global HIV epidemic. It can be divided further into nine distinct clades (subtypes or strains), each with their own genetic identity. The genetic diversity between different virus envelope protein, the critical target for antibodies, is 35%.
Clades A-D are the most prevalent globally; F-H, J and K are less prevalent. There are additional forms of HIV that result from more than one clade mixing to make either forms that circulate in three or more people who have no direct epidemiological connection (called CRFs) or unique forms (called URFs).
HIV Clade C is responsible for four times more infections than any other HIV-1 subtype. It is mostly found in southern Africa (where it causes 98% of infections), Ethiopia and low-income regions of India. However, it is increasing in eastern Europe and eastern Africa. Most early HIV research focused on Clade B, which is responsible for only 12% of infections and prevalent in western and central Europe, Latin and North America and Oceania. More recent studies had a major focus on Clade C and B.
Figure 1: The map shows the prevalence of HIV-1 Group M clades across the world. [Ed: See note in powerpoint slide] Source: https://journals.lww.com/co-hivandaids/fulltext/2019/05000/hiv_subtype_diversity_worldwide.3.aspx

Broadly neutralizing antibodies
As mentioned, bNAbs are being studied as prospective preventative tools because they have the potential to stop infection by a broad range of HIV strains or clades in the laboratory. As well as being studied as potential prevention, passive immunization with bNAbs is being explored as a therapeutic strategy for people living with HIV.
Many in the field believe that a product that could actively stimulate the body to produce its own bNAbs could prevent HIV infection. Based on current knowledge of the ability of how the immune system protects against HIV infection, bNAbs are becoming a key strategy in HIV prevention studies.
It is thought that combinations of three to four bNAbs targeting different HIV antigens will be needed to fully overcome the genetic diversity of multiple HIV-1 clades. Getting a product to induce a broadly active set of bNAbs is a highly challenging task and, therefore, needs a huge collaborative effort.
Although the bNAb approach is at an early stage, they have the potential to be more easily administered and potentially more affordable.
How were bNAbs discovered?
Research on bNAbs was made possible by the discovery and isolation of many hundreds of bNAbs from epidemiological studies of people living with HIV early in the epidemic.
Because they develop only rarely during infection, researchers needed to study many thousands of blood samples over the past decade and use new techniques to isolate the bNAbs.
Pipeline of bNAb studies in humans
There are of two types of studies using bNAbs in the pipeline, both aiming to prevent HIV infection. The first approach involves the direct infusion of bNAbs (so-called passive immunity). The second is to stimulate the immune system to produce its own bNAbs (active immunity). They are described in more detail below.
Approaches that are passively administering bNAbs include the use of: natural monoclonal antibodies; synthetic bNAbs designed to have increased potency and breadth of activity against HIV clades and to be active for longer; and combinations of bNAbs capable of recognizing multiple regions of HIV envelope or that have different levels of potency against different HIV isolates.
Passive immunity studies
The potential of bNAbs to prevent or treat HIV through passive immunity is actively being explored.
For example, the Antibody Mediated Prevention (AMP) Studies are looking at the efficacy of a bNAb called VRC01. Two Phase 3 studies, one involving men and the other women, are running concurrently across 11 countries.
The trials – carried out by the NIAID HIV Vaccine Trials Network (HVTN) and HIV Prevention Trials Network (HPTN) – are assessing passive immunization using a bNAb infused intravenously via a drip to see if it can protect against HIV infection in humans as it does in animal models. See the AMP factsheets for more information.
The International AIDS Vaccine Initiative (IAVI) has three passive immunization trials underway, all involving bNAb administration. They are T002 (Phase 1), T003 (Phase 1/2a) and C100 (Phase 1/2). Trials supported by the Bill and Melinda Gates Foundation are 3BNC117 (Phase 2) and in combination 10-1074 (Phase 1).
NIAID is sponsoring Phase 1 trials of another bNAb called VRC07-523LS, a new generation of VRC01 with increased potency. A recent report showed it to be safe and well tolerated in human volunteers, and further studies are underway.
As mentioned, it is likely that combinations of bNAbs targeting different HIV antigens will be needed to overcome the genetic diversity of HIV. To this end, two other bNAb (VRC07-523LS and PGT121) are currently being studied in Phase 1 trials involving women in South Africa.
Active immunity studies
How a bNAb approach to active immunity could work
Approaches to active immunity have often focused on “sequential immunization” (where the products are given in a sequence over time). Different HIV antigens are administered with the aim of guiding immune system B cells to produce different types of bNAbs over time (Figure 3). This contrasts with the approach used for the human papillomavirus (HPV) vaccine, for example, where identical HPV antigens are given in a sequence.
The GT1.1 Phase 1 study (full name BG505 SOSIP.GT1.1), sponsored by IAVI, is due to start recruiting 48 HIV-negative adult volunteers in 2020. This “first in human” study aims to determine both the safety of this synthetic HIV envelope protein candidate and the body’s antibody response to it after sequential administration.
GT1.1 is a synthetic protein engineered to mimic the natural envelope protein trimer seen on the surface of HIV. The trimer targets predecessors of immune system cells that have yet to be exposed to antigens – called germline B cells – and primes them to develop into bNAb-producing factories, with each cell producing its own specific type of (monoclonal) antibody.
These new B cells are stimulated repeatedly with GT1.1 with the aim of guiding them to produce a variety of different and unusual bNAb types and progressively increase the neutralizing strength of the antibodies they produce (see Figure 3).
IAVI G001 is one of four additional Phase 1 studies run by IAVI that are due to start at the end of 2020. It aims to evaluate the safety and immune response to an engineered sequence of amino acids (called eOD-GT8) that mimics the envelope protein and stimulates cells towards producing bNAbs.
While at an earlier (pre-clinical) stage of development, a type of genetic material called RNA is also being explored as a potential way to deliver antigens designed to induce bNAbs.
Conclusion
bNAbs are capturing the imagination of the HIV vaccine field because of their potency and ability to target the diversity of HIV clades. For bNAbs to have an impact on the HIV epidemic, they must be developed and deployed in a manner that supports broad access globally.
The potential of bNAbs and mAbs to treat and prevent infectious and neglected diseases is enormous. Although several mAbs targeting infectious diseases are licensed, there is a huge access gap, with 80% of sales taking place in the US, Canada and Europe while 85% of the population most vulnerable to infectious diseases are living in low- and middle-income countries.
With a rapidly increasing pipeline of new bNAb– and mAb-based products for HIV and other infectious diseases, planning for how to bring these products to people that need them most is critical. To this end, IAVI has teamed with Wellcome to produce a report entitled Expanding Access to Monoclonal Antibody-based Products, with a call to action to the global health community to ensure equitable access to mAbs and bNAbs.
After decades of research and development, a safe and globally effective HIV vaccine remains a challenge. However, new strategic approaches, including passive immunization, are in clinical development and may significantly contribute to HIV prevention strategies. The AMP studies aim to provide proof of concept for using a bNAb to prevent HIV infection. Results from AMP are expected in early November-December 2020.
The HIV field is communicating, cooperating and collaborating as never before, and all recognize how important this approach will be for the success of the bNAb approach. The excitement is palpable.
Barton Haynes, Professor of Medicine and IImmunology at Duke University, has said that if each team makes one or more complete and successful sets of sequential bNAbs, they can be combined into a successful product, possibly as soon as 2025-2027.
Glossary
A
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
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.
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.
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.
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
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.
Pathogen: A pathogen is an organism (for example, a bacteria or virus) that has the potential to cause disease.
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.
T
Trimer: See Envelope protein trimer (gp140).
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.
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
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.
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
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.
Pathogen: A pathogen is an organism (for example, a bacteria or virus) that has the potential to cause disease.
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”.
Protein-based vaccine: This vaccine is made up of a protein antigen designed to trigger an active immune response.
T
Trimer: See Envelope protein trimer (gp140)
V
Vaccine candidates: These are potential vaccines being tested in clinical trials.
Viral vector: This virus does not cause disease in humans and is used as a vehicle to transport vaccine ingredients into the body.
About
Established in 2003, the Global HIV Vaccine Enterprise (the Enterprise) became a programme of IAS – the International AIDS Society – in 2018. The Enterprise unites stakeholders to share knowledge, foster collaboration, enable solutions and expand support critical to the development of – and future access to – an HIV vaccine.
Global HIV Vaccine Enterprise
IAS – the International AIDS Society
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