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The Rise of Broadly Neutralizing Antibodies

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Bill Snow
Thursday, May 17, 2018
Antibody Related Research, HIV Vaccine

Bill Snow founded AVAC and is the former Global HIV Vaccine Enterprise Executive Director.

Research on broadly neutralizing antibodies (bNAbs) is taking the field of HIV prevention science in new directions, with implications for new prevention interventions and vaccine development. There’s much to know and much to learn about these powerful instruments of the immune system.

Since 2016, more than 2,700 men in Brazil, Peru, Switzerland and the US, and 1,900 women in Southern Africa have begun to enroll in clinical trials looking at antibody-mediated prevention, or AMP (see Figure 1). A collaboration between the HIV Prevention Trials Network (HPTN) and HIV Vaccine Trials Network (HVTN) (both funded by the National Institutes of Health), the AMP studies test the safety and efficacy of the broadly neutralizing antibody (bNAb) VRC01 when it is given every 8 weeks to reduce the risk of HIV infection. But how did this approach come about, why is it important and what may happen next with bNAbs for HIV prevention?

Click to enlarge.

What’s an antibody?

Antibodies are Y-shaped proteins produced by B cells to clear infected cells and pathogens in the bloodstream. B cells are part of what is known as the adaptive immune system, which mounts defenses aimed at specific invaders—like a cold virus or chicken pox or HIV. The innate immune system also defends against invaders, but its defenses are not so finely tailored to a specific pathogen. When a virus encounters the right B cell, the B cell begins cloning itself and produces antibodies designed to battle that virus. These antibodies circulate throughout the body looking for the virus, and they evolve continuously, becoming ever more precise and numerous.

The Antibody Hierarchy

Here are some terms that will help you follow this ongoing story:

  • Antibody: Proteins produced by B cells as a major part of the adaptive human immune defense against specific invaders.
  • Binding antibody: An antibody that attaches to a virus but doesn’t necessarily render it ineffective; can be driven by the innate immune system.
  • Monoclonal antibody: A bioengineered antibody made in a manufacturing facility by copying (cloning) one original antibody—selected for its potency and other characteristics.
  • Neutralizing antibody: Antibody that disables virus.
  • Broadly neutralizing antibody: An antibody that neutralizes many different genetic variants of HIV.
  • Passive antibodies: A dose of monoclonal antibodies that are infused or injected, rather than made by one’s own immune system.

How does HIV interact with our immune systems?

HIV prompts major responses from both the innate and adaptive immune systems, including an active effort to make antibodies specific to the virus. But, in individuals living with HIV, these defenses do not ever gain the upper hand. There are many reasons for this. Some antibodies target parts of the virus that are not critical to its ability to infect new cells. Other antibodies are effective, but not against the virus that is present in the body.

Consider this: sometimes people living with HIV have antibodies in their blood that are highly effective against the virus that they had at an earlier time. HIV mutates as it copies itself, and those mutations outpace the antibody response. Scientists sometimes say that, “Today’s antibodies can neutralize yesterday’s virus.” Why are they so late? Antibodies against any pathogen go through a series of changes that make them better and better at finding and blocking a given invader. This “maturation process” can take many months or years.

Antibody-mediated prevention, AMP, involves delivering those effective antibodies to people before they are exposed to HIV.

What are HIV-specific bNAbs?

When HIV mutates, it changes rapidly inside a person’s body. But there is also an enormous degree of genetic diversity across all types of HIV found around the globe. Ideally, an effective HIV vaccine would provide protection against virtually any strain a vaccinated person is exposed to.

This is why it was considered a huge breakthrough when, in the 1990s, scientists came across four rare antibodies that could neutralize a broad range of HIV strains. Then in the early 2000s, scientists found ways to screen an enormous number of individual cells from blood samples to find more of these bNAbs. It turns out they’re not so rare after all. Twenty percent of people living with HIV eventually make a few through trial and error mutations, though it often takes years, which is too long to provide benefit for the individual who ultimately makes them. However, this work—which involved many people living with HIV volunteering for research—has identified dozens of bNAbs precisely targeted to a handful of vulnerable parts of the virus.

Scientists are trying to create a vaccine that would teach the body to make bNAbs. It is a familiar approach. Most licensed vaccines teach the body to make neutralizing antibodies. What level of these antibodies must be in the blood to protect against HIV is not yet known, and it is a crucial question to answer in HIV vaccine research.

Antibodies as prevention products

How can scientists learn more about reducing risk of HIV with bNAbs? One approach is to test what happens when a person receives the protective antibody directly, via an infusion or injection. That’s what the AMP trial is testing, using bioengineered bNAbs known as monoclonal (all identical) antibodies (mNAbs).

Monoclonal antibodies aren’t just a phenomenon in the field of HIV. Other monoclonal antibodies, mostly for treatment of other serious diseases, are being used in many areas of medicine thanks to technologies developed in the 1970s and 80s that make it possible to produce large quantities of them quickly. If you hear about some great new “drug”, and its generic name ends in “ab”, it’s an antibody. mAbs have very few if any side effects. Companies can make antibodies against certain rare diseases under patent and charge extremely high prices. Consequently, innovative work is being done to make therapeutic monoclonal antibodies more potent, last longer and cost less.

Common Antibody Nomenclature

Ab – Antibody (singular, antibody)
Abs – Antibodies (plural)
mAb – Monoclonal antibodies (cloned antibodies, all alike, not necessarily neutralizing)
NAb – One neutralizing antibody
bNAb – One antibody that neutralizes many HIV strains
bNAbs – Broadly neutralizing antibodies (usually monoclonal is assumed, but depends on context when speaking of more than one bNAb type)

The last few years have been spent mapping and improving isolated HIV bNAbs in order to manufacture and administer them in quantities that may control or protect against the virus in people. BNAbs tend to target regions of the virus that don’t mutate (known as a conserved regions). If one could put together multiple bNAbs, each of which targets a different sensitive region, they might be able to block infection even more effectively.

One of the first monoclonal HIV bNAbs, VRC01, is being used in the AMP trials. In lab studies, VRC01 blocks about 80 percent of HIV strains circulating worldwide. Among monoclonal bNAbs, it is furthest along in development as an experimental approach for HIV prevention. VRC01 was developed by the Vaccine Research Center (VRC) at NIH, and it’s being used in the AMP trials as a test case to see how well monoclonal bNAbs work to protect people against HIV.

What is the AMP study testing?

1. Will the VRC01 antibody work to prevent infections?
This is important in its own right. If an infusion of monoclonal bNAbs protects against HIV, known as “passive immunity”, this could represent another important prevention tool. This may not be VRC01 in its current form—it’s more likely that this would involve combinations of monoclonal bNAbs, each targeting a different conserved region of HIV.

2. What’s an effective dose?
Unlike vaccines that teach the body to generate antibodies, antibodies given passively wash out of one’s system over time, like a drug. The level will wane in measurable ways. The AMP trials are testing a high and a low dose, based on data from Phase I studies in humans, and animal data. By looking at antibody levels of both high and low doses over time, results will show the level below which protection is lost.

3. How long will infused bNAbs work?
The infused monoclonal bNAbs eventually degrade. If the AMP study shows protection and the level of antibody needed for this protection, then measuring the half-life of the bNAbs will point the way toward establishing dose and frequency of a given infusion to maintain protection. (In addition, those viruses that escape VRC01 can be identified and targeted with additional antibodies.)

Other Uses

HIV-specific bNAbs could also be used as a supplementary tool for reducing the risk of mother-to-child infection, also known as vertical transmission. The risk of vertical transmission from women during pregnancy, delivery and breastfeeding can be reduced to less than 1 percent if the pregnant woman is on antiretrovirals and virologically suppressed during her pregnancy and after delivery.

Access to antiretroviral treatment (ART) for women living with HIV is essential for their own health and because of its prevention potential. But there are still instances when pregnant women do not learn their status, do not choose and/or are not able to take antiretrovirals during pregnancy or after birth. It takes time to achieve virologic suppression once ART is started, so the protection is not immediate for a baby in utero or after delivery. In that context, other strategies to reduce risk of onward transmission are needed and bNAbs could play a role with improvements in dosing, side effects and time to protection.

Next-Generation bNAbs

Next-generation antibodies are engineered to have a longer half-life, maintaining high levels for 4-6 months. At least six Phase I trials investigating combinations of monoclonal antibodies will be ongoing over the next two years, with results anticipated by the time the AMP studies release findings in 2020. Along with ongoing trials investigating protection—from long-acting antiretroviral drugs injected every two months and two HIV vaccine efficacy trials—trials testing a bNAb injection that last 4-6 months could be another form of injectable prevention.

BNAb research and development remains a long-term prospect, but lately it has been moving relatively quickly. There are several groups developing different bNAbs and mixtures for future testing, including researchers at the VRC, Rockefeller, Harvard and Duke Universities, IAVI, the Scripps Research Institute and CAPRISA. Both the NIH and the Bill & Melinda Gates Foundation are investing in this work.

All long-acting methods—from long-acting ARV drugs to monoclonal bNAbs and vaccines—need to be evaluated for cost, acceptability, feasibility and use in the real world. When it comes to studying antibodies, industry is leading the way with improved antibody production for other diseases, promising rapid advancement in manufacturing and cost effectiveness.

The immediate rewards for prevention, however, will come from what we learn in the meantime from trials such as AMP and similar studies over the next few years.

Here Are The Takeaways:

  • Great progress is being made in the antibody field overall.
  • Broadly neutralizing HIV antibodies could have a high probability to be a potent form of prevention and possibly treatment. Just this year the first bioengineered bNAb (in this case it’s not monoclonal, it’s one antibody that’s been engineered for two targets on HIV) called lbalizumab, was approved by FDA as treatment for people living with HIV for whom other drug combinations are no longer effective.
  • BNAbs trials could be an important step toward designing an HIV vaccine.
  • Broadly neutralizing monoclonal antibodies may be useful as prevention products, but that depends on the cost, dose, and the level of protection achieved.
  • All of this is in the works and in early 2020, AMP trials will have initial results.
  • Antibodies that neutralize “conserved regions” of HIV (areas of the virus that do not tend to mutate), and are administered in different combinations, are in clinical trials or moving towards it.