A committee asks age-old questions about immunity as they set out to look at how the delicate and complex immune systems of infants and young children might help inform AIDS vaccine development.

By Mary Rushton

In the decades-long search for a safe and effective AIDS vaccine, scientists have developed and tested dozens of different candidates, involving many different strategies. So far these efforts have been met with limited success. In 2009, results from the RV144 trial in Thailand showed a modest 31.2 percent efficacy against a prime-boost candidate that many AIDS researchers thought had a slim chance of working at all (see Special Report: Thai Trial Results, IAVI Report, Sep. 1, 2009). But the vaccine candidates—a canarypox vector-based ALVAC-HIV in combination with a genetically engineered version of gp120—tested in 16,000 individuals at risk for HIV, did not meet the criteria to warrant licensure. No other candidates have demonstrated any efficacy at all.

There are many reasons why it is so difficult to develop a highly effective and durable AIDS vaccine that could confer immunity against the vast numbers of circulating strains of the virus. One is that scientists have not yet been able to successfully design a vaccine capable of inducing broadly neutralizing antibodies (bNAbs) against HIV’s many diverse strains because our immune systems are generally outmatched by the virus. The field also suffers from the limitations of animal models that do not perfectly mimic what occurs in humans following HIV exposure.

There are other reasons for sure, but it is an open debate whether one of those reasons is that researchers are focusing too exclusively on developing and testing vaccine candidates for, and in, adults, rather than exploring ways to study the evolving and maturing immune responses in younger individuals. That was one of the questions that percolated in September when the AIDS Vaccine Research Subcommittee (AVRS), an advisory panel that provides advice and makes recommendations to leaders at the US National Institute of Allergy and Infectious Diseases (NIAID), devoted a whole day to the topic of pediatric HIV vaccine development.

Mary Marovich, director of the Vaccine Research Program in the NIAID Division of AIDS, says the discussion at AVRS was sparked in part by recent human and animal data, including compelling evidence that HIV-infected infants generate bNAbs faster than HIV-infected adults (Nat. Med. 20, 665, 2014).

“I was trying to be provocative with our experts… to push them to begin to think about whether we are in a situation where we could look at using and testing existing immunogens, as long as they are safe in adults, in an early life immunization strategy,” says Marovich.

The International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT), supported by NIAID, and the US National Institute of Child Health and Human Development have done early stage HIV vaccine trials in much younger volunteers. And a group of NIAID-funded scientists led by investigators from the Duke University Human Vaccine Institute have been studying neonatal immunity in nonhuman primates vaccinated with HIV vaccine candidates for the past several years, as have researchers at the University of California at Davis.

But the AVRS wants to take this idea further. The September meeting spurred promises from the committee to form a working group populated by representatives from child health groups and HIV vaccine networks. Marovich says the working group, which she expects to be organized by January, will examine the immunization landscape over the next 18 months and determine which, if any, of the immunogens that have already proven to be safe in adults could reasonably be tested in children, and if so what would be the appropriate age to immunize.

“The AVRS meeting was about whether we should develop a research agenda in this area. The working group will be more about how to do this and who is going to do it,” says Marovich. “While we are not actively discussing doing pediatric efficacy trials now, we can do Phase I safety studies and the bridging studies once we have a signal in adults.”

Just what immunogens might be tested in Phase I pediatric HIV vaccine trials, however, remains an open question. Currently, there are only two HIV vaccine efficacy trials in progress. One, a Phase IIb test-of-concept study known as HVTN 702, is evaluating a prime-boost regimen that is based on the one used in the RV144 trial. The study is enrolling 5,400 high-risk men and women in South Africa. Last month another Phase IIb study began in South Africa testing a prime-boost regimen developed by the Ragon Institute of Massachusetts General Hospital, the Massachusetts Institute of Technology, and Harvard, advanced to clinical trials by Johnson & Johnson’s Janssen Pharmaceutical Companies, the Bill & Melinda Gates Foundation, and NIAID. The trial’s organizers plan to include four other countries in southern Africa pending regulatory approvals. The study, known as Imbokodo (the Zulu word for rock, part of a South African proverb that refers to the strength of women and their importance in the community), is evaluating an adenovirus serotype 26 (Ad26) viral vector vaccine candidate containing four mosaic antigens engineered to provide optimal coverage against all circulating HIV variants, in combination with a clade C gp120 vaccine candidate.

There are many other scheduled or ongoing Phase I and II studies of vaccine regimens or antibody-mediated prophylaxis, including a study in HIV-exposed infants that will test whether bNAbs administered by injection are protective. Infants and toddlers are also a major focus of HIV cure research, given some of the recent findings that show very early initiation of antiretroviral (ARV) therapy in HIV-infected infants can result in undetectable virus levels for a period of years.

But to date, there have been no efficacy trials for HIV vaccine candidates conducted in infants or children, and the majority of safety and immunogenicity trials of preventive vaccine candidates developed so far have also been done in people 18 years of age or older. This is partly because HIV is primarily transmitted sexually or by sharing needles with an HIV-infected person. But Marovich questions whether researchers should consider vaccinating earlier. “Does it make sense to keep testing vaccines in adults after their sexual debut or to lower the age range to establish protection before they are exposed or during high-risk times like breast feeding?” she asks.

As Marovich points out, despite the overwhelming success of preventing mother-to-child transmission (PMTCT) of HIV, children are still vulnerable to the virus during the breast-feeding period. PMTCT is credited with helping to prevent 1.6 million new infections since 1995, a 2016 Joint United Nations Programme on HIV/AIDS (UNAIDS) report says. Cases of perinatal HIV transmission have declined by more than 90 percent in the US, according to the US Centers for Disease Control and Prevention (CDC), and there are 60 percent fewer children being newly infected in sub-Saharan Africa since 2009. Yet there are still thousands of children acquiring HIV from their mothers. A recent UNAIDS report estimates that every year 110,000 children are being newly infected with HIV in 21 sub-Saharan countries, with more than half of these infections occurring during the breast-feeding period. “In areas where the epidemic is still raging on, there have been good efforts and success in preventing mother-to-child transmission, but there are still gaps,” says Marovich. “There are still approximately 200,000 infants [worldwide] that are infected each year with HIV because they are born to infected mothers. For whatever reason, they were late presenters [to care], or adherence to ARVs post-birth was poor, or it happened through breast feeding. So it is still an issue globally.”

Past studies

Early on, before the dawn of ARV-based PMTCT, researchers were interested in testing vaccines to see if they could protect infants from the virus. In the early 1990s, a dose-escalation vaccine study led by New York University was conducted in 126 HIV-uninfected infants born to HIV-infected mothers in the US. The infants received four doses of recombinant HIV gp120 vaccine candidates developed by either VaxGen in partnership with Genentech, or Chiron, now part of Novartis, to see whether these HIV antigens were immunogenic. One regimen involved giving a dose at birth and then at one, three, and five months of age, while another more accelerated regimen started with a dose at birth, and then others at two weeks, two months, and five months of age (J. Infect. Dis. 181, 890, 2000).

At the end of the study, immune responses were detected in over half the infants after the second dose and those responses persisted for 104 weeks, with stronger responses observed in infants given the accelerated regimen. But three years after this study, two Phase III trials in men who have sex with men (MSM) and injection drug users testing the VaxGen recombinant gp120 candidate failed to demonstrate any efficacy (J. Infect Dis. 192, 974, 2005). This brought an abrupt end to any discussions about studying the regimen further in infants.

Plans to test another HIV vaccine candidate in breast-fed infants were also abandoned after the candidate failed to prevent HIV infection in adults. A collaboration between the Elizabeth Glaser Pediatric AIDS Foundation, IMPAACT, the HIV Vaccine Trials Network (HVTN), and Merck was planning to test the company’s adenovirus serotype 5 (Ad5) vaccine candidate in the breast-fed infants of HIV-infected mothers in sub-Saharan Africa, but the trial was shelved after the Phase IIb test-of-concept STEP trial in MSM and high-risk heterosexual women evaluating the same vaccine candidate was stopped early for futility (see A STEP Back?, IAVI Report, Vol. 11, No. 5, 2007).

More recently, a small randomized, placebo-controlled trial known as HPTN 027 found that ALVAC-HIV vCP1521, one of the vaccine candidates used in the RV144 trial, was safe, well tolerated, and immunogenic in infants born to HIV-infected mothers in Uganda (J. Aquir. Immune Def. Syd. 65, 68, 2014). Another Phase I/II study known as PedVacc 002 was conducted in Kenya to determine the safety and immunogenicity of a Modified Vaccinia Ankara (MVA) viral vector-based vaccine candidate in infants born to HIV-infected mothers. The single, low dose was delivered intramuscularly to healthy, four-month-old infants. The study demonstrated that the vaccine was safe but not immunogenic (Vaccine 32, 5801, 2014).

Why immunize earlier?

Most preventive vaccines are administered to infants and young children, largely before age two, because the developing immune systems of young children are more vulnerable to infection with life-threatening viruses. The sooner children are vaccinated, the less likely they are to be affected by the diseases the vaccines protect against. And when vaccine coverage is high enough, as is the case with many childhood immunizations, it can help eliminate virus transmission almost entirely.

To accomplish this though, the immune responses to childhood vaccinations must be strong and durable enough to be protective for long periods of time, which is something that has eluded HIV vaccine researchers so far.

It is possible, however, that immune responses to HIV antigens may be stronger in infants than adults, which is one reason the AVRS is discussing the topic of infant trials. Barton Haynes, director of the Human Vaccine Institute at Duke University, says that while some aspects of the neonatal immune system are immature and slower to respond, it is clear that in response to candidate HIV vaccines, infant immune systems respond as well or even better than adults.

Julie Overbaugh, a researcher at the Fred Hutchinson Cancer Research Center who has studied the mechanisms of HIV transmission and pathogenesis extensively, says there is still a ways to go in understanding why this is the case. “We know surprisingly little about the differences in the way infants develop antibody responses compared to adults and need to know this to understand the best way forward.”

Recent studies from her lab detail the speed at which an infant mounts both neutralizing and binding antibody responses. Three years ago, Overbaugh published the first findings showing that some HIV-infected infants can rapidly mount a broad neutralizing antibody response to the virus, sometimes within the first year of life (Nat. Med. 20, 655, 2014), unlike the minority (10-20 percent) of adults who take two to three years on average to develop bNAbs following infection.

In collaboration with scientists in Kenya, Overbaugh’s lab tested the ability of serum from 28 HIV-infected infants enrolled in the Nairobi breast-feeding trial to see if it could neutralize a panel of viruses. Serum samples from more than 70 percent of the infants were able to neutralize one or more viruses from a different clade than the virus with which they were infected, in some instances within just 12 months after acquiring HIV. Serum from seven infants neutralized viruses across all four clades.

Building on these findings, Overbaugh’s team next isolated 10 neutralizing antibodies exhibiting low levels of somatic hypermutation (SHM) from an infant at around a year post-infection, including one bNAb with cross-clade neutralization capabilities that targeted the glycan-dependent N332 supersite on HIV’s Envelope (Env) protein that some bNAbs isolated from adults also favor. The low levels of SHM that the infant’s neutralizing antibodies exhibited suggest that neutralization breadth can occur without the much more extensive level of SHM that is evident in all adult antibodies isolated to date (Cell 166 (1), 77, 2016).

Work led by Duke University researchers indicates that neonatal immunization may also be helpful in skewing antibody responses to subdominant HIV epitopes. Six years ago, a study led by Haynes’ lab determined that the initial antibody responses that arise in HIV-infected people within 14 days of infection, and which target HIV Env’s gp41 protein, demonstrated cross-reactivity between gp41 and the gut flora. The hypothesis was that the early response to gp41 was really a secondary response triggered by a pre-existing pool of memory B cells interacting with bacteria living in the gut (J. Exp. Med. 208: 2237, 2011; Cell Host Microbe 16, 215, 2014). Next his group studied samples from vaccinees in the Phase II and IIb HVTN 505 trials of a DNA/rAd5 vaccine candidate that contained Env gp41. This analysis showed dominance of the vaccine-induced antibody repertoire to gp41 with antibodies that cross-reacted with intestinal microbiome antigens (Science 349: aab1253-1, 2017). They went on to isolate gp41-microbiome cross reactive antibodies before vaccination, demonstrating microbiome-reactive B cells are expanded by HIV Env vaccination. Because intestinal microbiota shape the B-cell repertoire from birth, the researchers concluded that neonatal immunization with HIV envelope antigens may be able to imprint the B-cell repertoire to respond to antigenic sites on HIV Env that may otherwise be subdominant or disfavored, such as the broadly neutralizing antibody epitopes on HIV Env.

More recently Haynes’s group tested the same DNA/rAd5 vaccine regimen in neonatal rhesus macaques that was tested in the HVTN 505 trial, which was halted after failing to demonstrate efficacy in 2,504 MSM and transgendered women who have sex with men at 21 sites in 19 US cities (see Large AIDS Vaccine Trial Shudders to a Halt, IAVI Report blog, April 26, 2013). One of the objectives of the study was to see if gp41 immunodominance could be avoided by immunizing neonatal rhesus macaques during the early stages of microbial colonization (J. Virol. 91 21, 2017). They found that colonization of neonatal macaques occurred within the first week of life, and immunization of the animals during this time also induced a dominant gp41, microbiome cross-reactive antibody response, indicating that early vaccination could not overcome gp41 dominant responses.

Yet a retrospective study led by Sallie Permar and Genevieve Fouda, also with the Duke Human Vaccine Institute, found that infants were able to mount robust, durable Env-specific IgG responses, including anti-V1/V2 IgG responses, following vaccination with a recombinant gp120 vaccine candidate coupled with the adjuvant MF59, a potent oil-in-water emulsion made of squalene found in sharks and plants (J. Infec. Dis. 211(4), 508, 2015). This study assessed the binding and functional antibody responses in HIV-exposed vaccinated infants from historical samples collected as part of the Pediatric AIDS Clinical Trials Group 230 and 326 protocols, which were conducted in the US during the 1990s. While the study conducted by Permar’s group did not establish whether Env vaccination of infants would have been equally or more effective than HIV Env vaccination of adults, it did show they were capable of mounting robust antibody responses, including against the V1/V2 epitope that was an immune correlate of risk in the RV144 trial. They also tested samples from adults immunized with the same vaccine and found that the magnitude of the V1/V2-specific IgG response was higher in infants than in adults. (J. Virol. doi: 10.1128/JVI.01070-17).

Overbaugh says the idea of developing an AIDS vaccine for children is definitely worth thinking about, but added that there is still much to learn about how different types of immune responses are formed at this age in response to the virus. “In our study of breast-feeding infants we found that they developed broader and more potent antibodies rapidly [compared to adults], and a South African study found the same thing. So the interesting possibility that infants have an ability to make these antibodies quickly is, I think, incredibly important to study,” she says. “This could mean that vaccinating infants is the way to early protection, but it could also be that what happens in an infant is fundamentally different, and shaped by the mother’s antibodies passed on through breast milk.”

Sharon Nachman, chairman of IMPAACT and professor of pediatrics at Stony Brook University School of Medicine who was present at the AVRS meeting, agrees that there are many open questions about testing HIV vaccine candidates in infants. “What do we know about infant immunity? What do we know about child responsiveness and what do we know about the vaccines themselves that will help inform the right vaccine and the right vehicle to put the vaccine in?” asks Nachman. “These are some of the key scientific questions that were the focus of the AVRS meeting.”

Clues from animal studies

Recent findings in animal studies also offer clues about early life immune responses to HIV and HIV vaccines. Inarguably, one of the biggest challenges in AIDS vaccine development has been finding immunogens that reliably induce bNAbs to HIV. But a recent study led by Devin Sok, Antibody Discovery and Development Director at IAVI, managed to do just that by immunizing four calves (Nature 548, 108, 2017). When the animals were injected with a BG505 SOSIP trimer, all the calves developed bNAbs to HIV in their blood as rapidly as 35 to 50 days following two inoculations. This was a significant improvement from previous studies in rabbits in which the BG505 SOSIP trimer, while inducing neutralizing antibody responses against an autologous strain, was unable to induce bNAbs against the harder to neutralize Tier-2 viral strains.

What wasn’t widely known, says Marovich, is that the cows were all six months old. Whether age was a factor in the robust response is unclear though. Sok has his doubts that it mattered that much. “I don’t expect a difference between infant and adult cows because both have the same antibody repertoire,” says Sok. “It’s the antibody repertoire that’s unique from other animals.” But Marovich says a comparable study being done in adult cows could shed light on this question.

Planning for a trial

“Given what we are learning about the babies’ immune systems and their antibody responses to HIV, I think they are fully capable of responding to candidate vaccine immunizations,” says Haynes. “It’s perhaps useful to consider immunization of babies with an HIV vaccine candidate to try and understand in greater depth how babies respond.”

Ultimately, Nachman thinks the way forward for AIDS vaccine development will need to be multi-pronged. “In any epidemic, thinking about one vaccination time-point is the least effective. In order for an epidemic to change course you have to target all ages at different times, and not necessarily with the same vaccine candidate.”

She also thinks the surprise of RV144 is a good lesson for people to remember when deciding whether immunizing children is a path worth exploring. “If there is anything that RV144 has taught us it is that assumptions of how we think about vaccines are not always the right ones.”

Yet Nachman also emphasizes ethical considerations of testing vaccine candidates in children. “You have to have good reasons to bring a vaccine into children,” she says. “A region with a 40 percent acquisition rate of HIV would be a good place to do a vaccine study. It has to be a population of children where you can say it will do good and also do no harm.”

Mary Rushton is a freelance writer based in Cambridge, Massachusetts.

Implantable devices that can slowly and steadily release long-acting antiretrovirals into the body are one novel HIV prevention strategy now in development. Find out how a team of researchers at Northwestern University co-led by Thomas Hope is studying one such device.

By Kristen Jill Kresge

Ever since reading psychologist Barry Schwartz’s book “The Paradox of Choice: Why More is Less,” I came to believe that we are often crippled by the number of choices in daily life. Do I want the whitening toothpaste, or am I better off with the anti-plaque? Which of the 37 varieties of laundry detergent will actually work the best? That is just the beginning.

The proliferation of online shopping only seems to add to the confusion that endless choice creates. A simple search brings up dozens if not hundreds of possible options for any item you seek. And studies indicate that the more choices there are, the less likely you are to be happy with your decision. In fact, some studies even suggest the proliferation of choices may make people overall less happy than previous generations. There are plenty of TED talks on this topic, not to further overwhelm you with choices.

But in the world of HIV prevention research today, the prevailing argument is that people need more options. That is to say, researchers think offering more ways to protect against HIV infection will lead to more people actually using a preventive strategy that works for them. There are already a few choices: condoms, of course; adult voluntary male circumcision; and oral pre-exposure prophylaxis (PrEP, the use of HIV drugs to prevent HIV infection), which has been shown to be over 90 percent effective at preventing HIV infection when used consistently. But researchers say that the barriers are still too high to get many of the people who are at greatest risk of contracting HIV to use any of these options consistently and correctly, which is, of course, the only way they are effective.

This is why researchers are moving ahead to apply for regulatory approval for the vaginal ring containing the antiretroviral (ARV) dapivirine, which was found to be 27 percent effective in pooled results from two large efficacy trials (see HIV Field’s Current Contours Show in Boston, IAVI Report, Vol. 20, No. 1, 2016). It is also why they are investigating whether a regular injection of antibodies that can protect against many of the HIV isolates in circulation, so-called broadly neutralizing antibodies, can protect those who aren’t willing or able to swallow a pill every day to stay HIV free. Another option is using long-acting ARVs that will be applicable not only for treatment but for prevention as well (see Longer-acting HIV Prevention Methods: Take Two Antibodies and Call Me in Six Months?, IAVI Report, Vol. 21, No. 3, 2017). These long-acting ARVs could be delivered orally, by injection, or via an implantable drug-delivery system that could self degrade or be replaced annually, similar to the implantable hormonal contraception devices that last for three to five years.

It is this type of implantable device for HIV prevention that is the focus of a US$17.5 million grant awarded by the US National Institutes of Health to researchers at Northwestern University in Chicago. The five-year grant is funding the Sustained Long-Acting Protection Against HIV program, involving 15 basic scientists and clinical investigators across 15 departments at the University’s Feinberg School of Medicine, McCormick School of Engineering and Applied Science, and Kellogg School of Management.

One of the project’s principal investigators is Thomas Hope, professor of cell and molecular biology at the Feinberg School of Medicine. The other is Patrick Kiser, associate professor in obstetrics and gynecology at the Feinberg School of Medicine and biomedical engineering at the McCormick School of Engineering.

Hope is a familiar face in HIV research and a rather colorful character. He often delivers presentations at conferences around the world clad in a Hawaiian shirt, and always with an air of joviality. But the work he and his group do is serious. Much of it involves understanding mucosal transmission of HIV and the critical events immediately following transmission that allow the virus to establish persistent infection. In addition to pushing forward the field’s understanding of the important interplay between HIV and multiple cell types, this research generates stunning, gallery-worthy microscopic images of the virus within the mucosal environment where infection is first established following sexual transmission.

Hope’s personality is perhaps most evident in the naming of Northwestern’s program to develop an implantable drug delivery system. “A lot of these trials have inspiring names like ASPIRE, ASCENT, et cetera,” he said recently at a meeting sponsored by the New York Academy of Sciences (NYAS). The program Hope co-leads is called the Sustained Long-Acting Protection Against HIV program, but it is the acronym that says it all. “We decided to take a more aggressive approach and call it SLAP HIV.”

Hope spoke at the NYAS meeting about his team’s efforts to develop an implantable device to deliver the investigational ARV cabotegravir, an integrase strand transfer inhibitor with potent antiviral activity that is being developed by Viiv Healthcare. Cabotegravir is one of the first drugs to be developed simultaneously for treatment and prevention. It is currently being tested as both an oral formulation and an injectable in a large prevention trial. And the goal of Hope’s program is to advance an implantable cabotegravir delivery system to Phase I clinical trials by the end of the five-year grant period that began in 2015.

We spoke in detail about the program and its progress, and also the other projects he currently finds most promising.

Can you start by explaining the implantable drug delivery system that your group is developing as part of the SLAP HIV program?

Basically, to make it you more or less compress the drug into a series of pellets and then you put the pellets inside of a membrane that is made from a polymer that is designed to let the drug leak out at a certain rate. You play around with the different polymers and you use the one that allows the drug to be released at the rate you need for protection.

It is interesting because you basically start with shelves of beakers with stir bars in them and you put the different prototypes of the implant in the beaker. Then you take a little bit of the liquid out and put a little liquid back in, kind of pretending the beaker is like a little system, and by doing this you can figure out how much of the drug is actually coming out. And then you make adjustments. Once you get close to the amount of drug being released every day that you want, then you move things over into, for instance, different animal studies.

And why work with cabotegravir?

Even though there are many, many antiretrovirals, there are only a handful of them that can work for a long-term, sustained-release strategy because the drug needs to be very potent, and it needs to be cleared from the system slowly. Cabotegravir is one drug that that can be accomplished with. The others that might work, at least on paper, are the Gilead drug known as TAF [tenofovir alafenamidem or Vemlidy; a drug approved by the US Food and Drug Administration for the treatment of chronic Hepatitis B virus infection] and the new Merck drug that they call MK-8591, or as I called it at the New York Academy of Sciences meeting, unobtanium, because they are not really sharing information about it with anybody. I thought they would be mad that I called it that, but they actually thought it was funny.

And then did they tell you all about the drug?

Well, that’s a different story, but the scientists from Merck did tell me they thought it was funny that I said that.

So you couldn’t take any drug or combination of drugs and use a similar system to what you have developed?

Well it is really about the drug’s potency. The implant needs to be small enough that it is not obtrusive. If you had an implant that was the size of a can of beer and you could put it under your skin somewhere, then you could use any drug. But the problem is the drug has to be very potent because the size of the device has to be small. You could probably only put hundreds of milligrams of drug in the little implantable device, and ideally, for an implant, you are looking for it to hold enough drug to last about a year in order for people to be willing to go through the surgery to insert the device. You can take a pill every day, but this is something entirely different. You have to have the device surgically inserted and then it has to be removed or replaced, and that is much more complicated than taking a pill. So for people to be willing to go through that, there has to be a real benefit. Therefore it really is potency of the drug that is the limiting step.

If you were going to use a different long-acting antiretroviral, such as TAF, could you just change the polymer that controls the release and modify your device to work?

Some technologies are readily adaptable to other drugs, but ours is very specific. Some people have devices that are more of a solid matrix with little holes drilled in it, but because ours is really just a tube of polymer and because each drug has different characteristics, the polymer that works best for TAF is not going to work for cabotegravir. There are other technologies that are being developed that are more universally applicable. For example there is one that is basically a metal tube that slowly pushes the drug out of one end, and so with something like that, you could use any number of different drugs because you are just pushing the drug out of a tube.

Where are you now in the development and testing of your implantable in animal models and what are the plans for clinical development?

Well, we are very anxious…the nature of this grant is that we are supposed to have a Phase I clinical trial completed by the end of the fifth year, or at least in the no-cost extension period, so we are trying to meet that. Right now we are transitioning from beakers into rabbits, and then into primates to see if the way these things seem to perform in these idealized systems within beakers translates to the living animal. Those studies are ongoing right now.

Where does the device go in the body?

That is a good question. It can kind of go anywhere but right now we are mostly thinking of doing something similar to what is done for Norplant and other hormonal implants used for birth control. Those devices tend to go in the inner arm, around the lower biceps. And the logic for that, although we have not been able to find out explicitly why they decided to put it there, is that it is a place that is not going to be exposed to outside impacts, you know, like being in a car accident and hitting it hard against the inside of the car or any other sort of bumping into something. It is a little bit protected in that place. But there has also been some discussion of putting it in the buttocks or in the small of the back.

You want it to be someplace where there are not a lot of nerves and you are not going to notice it. But right now as we are doing our acceptability studies, we show examples of it being like the hormonal, sustained-release devices and so it is in that same spot on the inner arm.

Is there also anything to be learned from the implantable insulin release systems that are used for treating diabetes?

Insulin is a much bigger molecule than these antiretrovirals, so while I think some lessons can be learned, like how the body reacts to implants and that kind of stuff, the actual functions of the devices are going to be very different for a human protein versus a small molecule. These drugs are very small molecules.

If you are trying to prevent against sexual transmission of HIV, how do you know how much of the drug needs to be in a person’s system to protect against exposure? Will cabotegravir released by the implantable device have a different bioavailability than if swallowed in a pill form or administered by injection?

So that’s the idea behind the animal studies. It all comes down to the systemic drug levels. When you take a pill, depending on the drug, either all of it gets into your system, or with some drugs, not that much of it gets into your system. And so the bioavailability is dependent on the drug getting through your digestive tract to enter your system. We do not have that issue with the implants.

And so the idea is after—we have to do all the studies, of course—but after a certain period of time, days or weeks, the drug would be spread throughout the body. We know from studies of oral PrEP and some other things, that sometimes these drugs concentrate in one part of the body and less in another part of the body, so that becomes important. You just have to have sufficient levels to provide protection, that is what it is all about.

Could you theoretically develop this type of an implantable device to allow the broadly neutralizing antibodies to be released over time, or is it really specific for non-protein, small-molecule drugs?

I do not think this technology with the membrane, where it releases the drug through the membrane, would ever work for broadly neutralizing antibodies. But people are developing technologies to accomplish this, it is just different kinds of technologies are required to make these things work.

Is there any interest in developing an implantable device for HIV treatment, or just for prevention?

You are absolutely right that this same exact device could be used for treatments, but in the grant program that is sponsoring this project, they were very explicit in saying you had to pick prevention or treatment, and because we have a lot more experience in prevention, we are focused on prevention. But the implant could easily be used for therapy.

What role is the management school at Northwestern playing in this grant? Are they involved in figuring out whether people would want to use an implantable device and how to market it?

So one of the things that the field is considering, and there is a lot of discussion about this, is how there have been all kinds of efforts to develop new products—vaginal rings, gels, et cetera—and then very often when it comes time to roll these new products out, the people that have to use them are not so excited about actually using a gel or a ring. Instead it is, “I would like this, but I don’t want it to be this way.”

So I think this program was set up really, very well. The first couple of years was a competition of different groups to see which one could develop a technology that made the most sense. And part of the decision process used to decide which of these technologies to advance into a Phase I clinical trial was going to be concerns about whether or not it would be used. If we have three technologies available that we can advance, and one of them people are excited about using for prevention, and the other two, they’re like, “I hate that idea,” then that would come into play. So the role of the School of Management has been in conducting acceptability studies.

Historically, as a hardcore scientist, I have not necessarily always been a big fan of this sort of work. But I am now convinced that it is of the highest level of importance. We need to start thinking about how we are going to get people to use these things and offer them the things that they are willing to use, otherwise we haven’t solved any problem.

Our number one guide in the management school, Bob Schieffer, is an expert in doing these kind of analyses. It starts with a focus group to get a sense of what people are thinking. Then you can turn that into hard science by doing something called a conjoint analysis and discrete choice analysis.

If you just tell somebody here are 10 things and say, “Which is your favorite one?” the responder might grab one, but then the next day they would grab a different one. And sometimes people don’t even know what they like or not. So instead of offering them—this is just one crude example—but instead of offering them 10 things to pick one from, you offer them the 10 different things two at a time. Then you can ask do you prefer this one or this one? This one or this one? This one or this one? And by doing this, some things become immediately apparent to analysts. One is that some people, like 15 percent of people, don’t know what they want so perhaps they can be excluded from the analysis. Then you can start to extract different information. Is their number one choice right next to their number two choice, or is their number one choice far superior to number two? These comparisons allow you to get this kind of information.

And then other choices are also very important. A good example is choosing between your favorite restaurant and your second favorite restaurant. The second favorite restaurant is across the street. Your first favorite is a 20-minute drive. You want to go to your favorite restaurant but it is raining, so you decide to go across the street. And then the next week the situation is different and you make a different choice. This example shows that the context of the things you have to consider when you make a big decision, or a small decision, are complicated and so you need to try to measure all of those things.

With the School of Management we’ve found a goldmine in my opinion. These people did this sort of work as a profession, they were successful and were able to retire, and now they are teaching the next generation by working in the School of Management. They can take those approaches and apply it to this very important area. Other people are of course doing this too, including the commercial firms that actually run the surveys.

I think that has been one of the several really neat things that have come out of this project that I was not anticipating.

Do people really need that many more choices when it comes to HIV prevention?

People often cite birth control as an example, in part because it’s sexually related, and in part because what actually works in getting people to use it more is having a choice of what method they want.

Back when there were very few choices, birth control was less successful. Now, there are all these different choices, even internationally, like rings, for example. Rings for birth control are much more popular in South America than anywhere else. In other parts of the world they aren’t used at all. In the US, I think contraceptive rings make up less than 10 percent of the market, maybe eight percent. That is still enough for the companies to make money on it, but it is not the top choice.

What we really need for HIV prevention is to offer people options. The implant is an option for individuals that are not good at taking pills every day. Some people are good at taking pills every day, whether it is for blood pressure or anything else, and other people are not. And bizarrely, if you do not take the pill, it doesn’t help you. From inside the bottle it can not do much.

What other areas of HIV prevention research are you involved in?

Right now I think we have the best science ever happening in our lab, and one thing that I think is very relevant is that we are doing some work on injecting broadly neutralizing antibodies and learning neat things about how they distribute in the body. We inject them into a macaque and watch how they distribute. By doing this, we are learning all these new ways that antibodies get to mucosal sites and the brain that nobody knew about before.

Some other work that I am really excited about is that we are finding there are all these unique interactions between antibodies and mucins [glycoproteins] in mucus that can add to antibody function, and in some ways, even change the functions of the mucins.

We are excited about being able to contribute to HIV prevention.

So does that bode well for the antibody prophylaxis studies, perhaps?

I am excited about those studies. I have to admit, a few years ago I was less enthusiastic, but the system has gotten so good at producing these antibodies at lower costs and modifying the antibody with certain mutations that make the antibody persist for a long time. I think some of that work that has been going on for a while is really coming together nicely.

Speaking of the interaction between antibodies and mucus, it reminds me of how your lab creates some of the most stunning images of the virus. I never knew mucus could be so beautiful!

It is really fun to have these pictures of what we do because people can look at them and kind of get a sense of what is going on. Your average person can appreciate those pictures more than, say, a flow cytometry plot, or a bar graph, or something else abstract. With the pictures you can show them that the green dots are viruses and all of the sudden they can visualize what is going on. So it is a nice space to operate in.

Perhaps a gallery showing is in your future?

We have thought about it and we have been involved with some of those. They had a show at the American Society of Cell Biology and they sold the pictures for charity. We gave them about 10 of our pictures and they used them all and they sold them all. So we do that a little bit. It’s fun.

You are also training and collaborating with early career researchers in Kenya, one of whom we profile in this issue. What inspired you to establish those connections?

I think it is very important, and we have to do these things. It helps establish contacts and collaborations because they have local knowledge that is important. They can help us to get highly relevant samples. We haven’t progressed that far yet where we are worried about this, but if we make a vaccine, we want it to work in Africa, and in the US, and everywhere else, especially in places where there is more transmission occurring. And there are differences in these populations that we have to understand and address. So these kinds of international studies are really important in the long run. One of the things we are doing is just trying to compare mucosal environments between volunteers in the US and Nairobi, Kenya. We are also trying to transfer some of our technologies to Kenya, and one of the cool things is they just got a microscope like ours, so that is exciting.

Nine years ago this month, we launched the redesigned IAVI Report. It was a major overhaul, introducing a new format, more varied content, and featuring our first full-color cover image. Ever since, we’ve collected and featured an array of images related to HIV on our cover. They are both striking and scientifically relevant as they are helping researchers understand more precisely how the virus behaves.

The image that graced that first cover is still one of my favorites. It showed an HIV-infected dendritic cell in the process of forming a virologic synapse, through which it would transfer HIV to a CD4+ T cell. Even though it obviously depicts a static moment in time, it feels active. The CD4+ T cell is being lured by a virus-infected cell, the synapse shown in a smear of red that seems to foretell the cell’s future destruction.

That cover was provided courtesy of Thomas Hope, professor of cell and molecular biology at the Feinberg School of Medicine at Northwestern University. His lab continues to churn out alluring images of HIV’s interactions and we are thrilled to feature another one of his group’s images on this issue’s cover. This one reminds me of an undersea landscape and is yet another example of how science makes great art. We also have an interview with Hope in this issue in which he discusses his team’s contributions to the development of a long-acting HIV prevention strategy meant to bridge the gap until a future vaccine should become available.

In a related story, a new writer to IAVI Report, Max Dorfman, profiles Marianne W. Mureithi, who apprenticed in Hope’s laboratory in Chicago and is now a chief research scientist at the Kenya AIDS Vaccine Initiative. Mureithi is one of many young African researchers who have returned home after studies abroad to contribute to ending the epidemic that has cost them so much personally.

In another feature, we provide an update on a topic the HIV vaccine field is currently grappling with—the possibility of conducting a vaccine trial in a pediatric population. The issue is not a new one but recent scientific findings, both in humans and animals, are causing researchers and funders to consider this possibility with renewed urgency. We also delve into the growing threat of antiretroviral resistance in developing countries and how this is raising concerns among public health experts about the fragility of the AIDS response and the need for improved prevention. This is undoubtedly an issue that will warrant consideration from Peter Sands, the newly appointed executive director of the Global Fund to Fight AIDS, Tuberculosis and Malaria.

Finally, as this year draws to a close, our team at IAVI Report would like to wish all of you a healthy, peaceful, and joyous new year. Year after year we are inspired and amazed by the innovative science we get to write about, the personal motivation that drives scientists and advocates toward an HIV vaccine, and the extraordinary commitment of those working tirelessly to end AIDS.

—Kristen Jill Kresge

Former Banker Looks to Boost Global Fund Resources as New Director

At a time when deft financial negotiations can seem almost as vital as basic research in providing access to lifesaving treatments and vaccines, Peter Sands may be a logical pick to head the Global Fund to Fight AIDS, Tuberculosis and Malaria. The former chief executive of Standard Chartered PLC, a global bank headquartered in London and involved in an unusually broad variety of financial businesses, comes into the job as a respected figure in both finance and public health.

“It’s an outstanding appointment,” says Ngaire Woods, founding dean of the Blavatnik School of Government at Oxford and an expert in global economic governance. Woods worked with Sands on a World Bank/Wellcome Trust project proposing ways for governments and development partners to finance and strengthen pandemic preparedness. She lauds his commitment to the effort. “He put in a huge amount of time, analysis, and writing. He’s low-key, listens extremely well, is a fantastic analyst, and a terrific communicator.”

Sands, a onetime non-executive director to the UK Ministry of Health, is slated to take the reins as executive director of the Global Fund in March. He will be taking charge of the world’s largest funder of anti-AIDS, tuberculosis, and malaria efforts. The Global Fund has distributed more than 795 million insecticide-treated bed nets in the fight against malaria, is supporting antiretroviral (ARV) treatment for nearly 10 million people living with HIV/AIDS, and has funneled more than US$17 billion in paid pledges from international donor governments to public health initiatives.

Long the front-runner to take the leadership role at the Global Fund after Mark Dybul stepped down last May after a four-year term, Sands takes over from Marijke Wijnroks, who has been acting as interim executive director and has been on the IAVI Board of Directors since 2011.

There were some hiccups in the process of selecting the Global Fund’s new executive director. Even before Dybul left as planned when his contract expired, the Global Fund suspended and then re-set its search for a new leader because donors were unhappy with how the process was being managed. It was then reported that Sands had taken his name out of the running only to re-enter the race just days before being appointed. And The Lancet recently reported that Sands received near-universal backing but did not gain support from the US—apparently due to Standard Chartered bank’s business transactions with Iran (Lancet 390, 2338, 2017). The US is the top contributor to the Global Fund, with its $13.2 billion pledged contributions ($12 billion of which had been paid as of 2016) making up 32.4 percent of the total pledges, according to Kaiser Family Foundation figures. This makes the relationship between the US and Global Fund a vital one for Sands to manage.

Ron Waldman, a global health professor at George Washington University who, among other things, once led the United States Agency for International Development preparedness unit for influenza and other pandemics, says the Global Fund is in a period of transition. “It was created to fill a void that the WHO [World Health Organization] allowed to develop, and as far as I can tell it did that. If we were starting from scratch and rebuilding the global health architecture, would it still have that place? I’m not sure,” he says. “There has been substantial donor investment in it, so that might be called a success. Will replenishment continue? That will depend on a lot of factors including perceived need and, if the need is there, to a large extent on Mr. Sand’s ability to convince donors that the Global Fund remains a worthwhile investment. He should be good at that.”

The Global Fund is a player in the recent price support deal struck by the Bill & Melinda Gates Foundation and the Clinton Health Access Initiative to bring the integrase inhibitor dolutegravir to 90 low- and middle-income countries, where it is expected to have a big impact in not just convenience and effectiveness but in beating back a worrisome threat of viral resistance to existing ARVs.

In a statement provided by the Global Fund press spokesman, Sands describes his background in economics, finance, and management as relevant to the challenges facing the institution, including sustainability. His priorities, as laid out in a recent commentary, are to raise the ambition levels for the Global Fund and deploy greater resources (Lancet 389, 2086, 2017).

“The most powerful argument that the Global Fund can bring to donors is impact: millions of lives saved along with a massive economic burden lifted and significant economic development in communities that have been held back by these diseases,” Sands says in the press statement. “We need to continue to make the case of proven delivery: that donor’s resources are well spent and delivered. We also need to make the case of the escalating benefit of being able to eliminate and stamp out these diseases both in countries and in key populations. There are always going to be pressures on government budgets and competing priorities, but the Global Fund starts in a strong place. We have shown we can make a huge impact.” —Michael Dumiak

Michael Dumiak reports on global science, public health and technology and is based in Berlin.

A New Wave of African Researchers at Work on HIV

Marianne W. Mureithi, lecturer and postdoctoral scientist at the University of Nairobi and chief research scientist at the Kenya AIDS Vaccine Initiative (KAVI), knew she wanted to be involved in the sciences, even from childhood. She recalls being fascinated by the human body, needing to know every organ’s function and purpose. “When I was really young, I was fascinated by biology,” Mureithi says. Yet it wasn’t until the 1980s, when HIV/AIDS hit her home country of Kenya, that she understood she had a calling. She lost several family members and friends to the epidemic. “I wanted to know why HIV was affecting people in sub-Saharan Africa. It was killing families and no one could understand why.” Even then she recognized that the lack of research centered in Africa would be a major detriment to solving HIV. So after receiving her PhD in Immunology & Microbiology at the University of Bristol in the UK, and pursuing her post-doctoral studies at Harvard University, Mureithi returned to Kenya with a plan to contribute however she could in defeating the virus.

Now she is part of a new wave of African researchers that is making steady progress in understanding HIV transmission in an effort to develop new and improved prevention strategies. She is also part of the surging movement to create sustainable, self-sufficient research in the areas hit hardest by AIDS. For Mureithi, her part in this movement is driven by both personal and intellectual concerns.

The HIV/AIDS epidemic is having particularly devastating affects among young women in Kenya. According to the latest data from the Joint United Nations Programme on HIV/AIDS, there is a significantly higher prevalence of HIV/AIDS among women aged 15-49 in Kenya than men of the same age—almost seven percent among women, compared to around four percent for men. This high prevalence among women necessitates a focus on prevention, Mureithi says, which is why she became involved with KAVI.

There, Mureithi is studying mucosal transmission of HIV by analyzing tissue samples collected from hysterectomies performed on HIV-infected female volunteers. This work is being done in partnership with Thomas Hope, professor of cell and molecular biology at Northwestern University’s Feinberg School of Medicine (see page 9), who mentored her. Mucosal surfaces are the first point of entry for the virus during sexual transmission. Understanding the role proteins, known as mucins, and other components of the mucosal environment play in providing a barrier—or welcome mat—to HIV is critical to attempts to block the virus. By observing how the tissues of the uterus and cervix obtained from HIV-infected women reacted to the virus, Mureithi and her team can more clearly illuminate the mechanisms by which mucosal immune responses slow HIV, with the hope that understanding and eventually triggering these responses can create a pathway to vaccine development.

Now Mureithi and her team will be able to conduct this research with cutting-edge technology. The newest addition to her lab is a high-powered deconvolution microscope, the same one that Hope’s lab is using in Chicago. It is one of the first of its kind in Kenya, and the region. It was provided through funding from the US Agency for International Development. This state of the art device allows Mureithi and colleagues to observe living cells, helping them understand in real time how HIV interacts with immune cells in various tissues. —Max Dorfman

Max Dorfman is a staff writer at IAVI based in New York City.