Erica Ollmann Saphire, PhD, is a structural biologist who studies viral molecular structures to develop frameworks for immune response medicine. As a professor at the La Jolla Institute for Immunology (LJI), Saphire has continued to shed light on the mechanisms by which these glycoproteins function, which is critical for understanding viral entry mechanisms, immunological function suppression, and the sites at which human antibodies can combat these infections.
Saphire’s work has helped to solve the structures of many viral glycoproteins, including those of the Ebola, Sudan, Marburg, Bundibugyo, and Lassa viruses. But one class of viruses—herpesviruses—has long eluded Saphire and, for that matter, the global immunology community.
That might soon change, though, thanks to a new national project spearheaded by Saphire at the LJI that has received up to $49 million to develop vaccines for herpesviruses that are major global health concerns. The project, named “America’s SHIELD: Strategic Herpesvirus Immune Evasion and Latency Defense,” is part of ARPA-H’s Antigens Predicted for Broad Viral Efficacy through Computational Experimentation (APECx) program.
“[America’s SHIELD] is a landmark opportunity to put together the tools that we needed on the scale that we needed to address the chronic health of the American population in a way that hasn’t been done before,” said Saphire. “I think for most of the professors, working on this project will be the most important thing we’ll have ever done in our careers.”
Saphire will work with collaborators at the LJI’s Center for Vaccine Innovation, including professor Chris Benedict, PhD, professor Alessandro Sette, PhD, and professor and chief scientific officer Shane Crotty, PhD. In addition, America’s SHIELD will include collaborators at Houston Methodist, Emory University, Drexel University, Brigham and Women’s Hospital, Louisiana State University Health Sciences Center, Dartmouth College, Massachusetts Institute of Technology, University of Southern California, Weill Cornell Medical School Emory Hope Clinic, the University of Texas at Austin, and the University of California, Davis.
Herpesviruses, the impractical jokers
Vaccine development has been somewhat cookie-cutter—grow, inactivate, and inject these submicroscopic agents, hoping to arm the immune system with an innocuous form of the virus. However, vaccine development is more complicated, akin to a paint-by-colors scenario but with a huge range of templates for pictures. Some are simpler, like using a couple of colors to paint a very low-resolution flower with just a few spaces to fill in. Others are far more complex, like a detailed shimmering sunset requiring an 8-bit RGB palette of 256 colors. This complexity in vaccine development stems from several variables.
The first is viral latency. On the one hand, Ebola and SARS-CoV-2 cause acute infections—a person becomes infected, recovers, and the virus is eliminated from the body. Some herpesviruses, on the other hand, can remain with a person for the rest of their lives, surviving for long periods in the cells they have infected, only to reemerge decades later to cause more havoc.
“These are not vaccines against viruses you might get—they’re vaccines against viruses you already have,” said Saphire. “It may be enough for the [Ebola and SARS-CoV-2] vaccines to knock down the amount of virus a few logs, and your immune system can mop up the rest. The trouble with these herpesviruses is that even if one or two get by and infect, you have a lifelong infection. So, it’s not enough to knock it down a couple of logs—you need to prevent infection, or what we call sterile immunity. But you have to clear all [the viruses], and that is just such a high bar; it’s really, really hard to get there.”
For instance, the varicella-zoster virus (VZV), which causes chickenpox, is known to cause this kind of infection, which can last a person’s entire life. Although a child may fully recover from chickenpox, it does not imply that the virus has completely disappeared. VZV can lie dormant in nerve cells for decades before resurfacing to inflict a painful case of shingles. In the case of Epstein-Barr virus, the resurfacing doesn’t cause a rash—it can cause cancer.
Saphire said, “You go to lock the front door, but unfortunately, the thief is already inside and going from room to room. It doesn’t keep out the bad guy already in there.”
The second significant variable is herpesviruses’ ability to infect cells with different receptors. To attach to and infect various cell types, cytomegalovirus (CMV) produces multiple receptors, such as gp350 and gp42, and removing them one by one does not prevent the virus from infecting cells.
“These darn things have multiple different surface proteins it can use to get in, and if your vaccine blocks one receptor, it’s going to use a different one,” said Saphire. “If your vaccine is focused on blocking entry, it’s like locking your front door but leaving all your side doors unlocked.”
A third related variable concerns the complexity of viral genomes. Viruses range in size from a few kilobases long and carrying a small number of genes to several megabases long and carrying hundreds—if not thousands—of genes. When a virus has more genes, it usually has more ways to infect cells, which means it can infect more kinds of cells, trick the immune system, and stay alive longer.
“There are things on the surface that mediate entry that nobody has uncovered yet,” said Saphire. “Maybe [the vaccines] will need multiple components—a lock on the front door, a lock on the side door, a lock on the back, or a lock in the garage door.”
As if playing a practical joke on vaccine developers, these herpesviruses only infect humans. That means that there are very few if any, useful preclinical models to study herpesviruses in the lab. According to Saphire, mouse herpes viruses and rhesus herpes viruses are similar enough to human ones to help validate the logic of particular vaccines approached, but not specific to vaccines that would be used in humans.
America’s SHIELD, herpesvirus avengers
The only way to untangle this collection of interwoven problems that has made herpesviruses so elusive to vaccine developers is a massive coordinated effort of specialized groups performing complementary research, which is exactly what America’s SHIELD plans to do. Some researchers, including Saphire’s group, which specializes in high-resolution imaging, will solve molecular structures of potential vaccine targets.
“We are uncovering how the different molecules of this virus are folded up, what is the target shape, and revealing how to hit them and target them and design the vaccine material,” said Saphire.
Some groups will analyze viral genomes and assign functions to open reading frames that have yet to be figured out, while others will use AI to design molecules to alter these targets to block the mechanisms for viral attachment and infection.
Saphire said, “There are many of these different viruses, and each might have different strains. If we can solve one’s molecular structures, can we start to predict how they will vary? What will be the same? Will artificial intelligence accelerate that design process and figure out how to stabilize the molecules so that they present the right structures?”
Another line of research will try to identify immune signatures to match vaccines to patient populations. Saphire said that America’s SHIELD would like to investigate utilizing data from new programs in New York and some other states that just started universal newborn screening for CMV.
“With all of those blood samples from mom-baby pairs, you can see are there immune signature differences between the moms that transmitted an infection and moms that didn’t transmit the infection, and that might set the bar for what we need a vaccine to achieve to prevent transmission to the baby,” said Saphire.
In a similar vein, Saphire is curious whether viruses retain surface signatures that the immune system can use to identify and eliminate them once they enter their late and lifelong stages.
According to Saphire, the key to effectively preventing the spread of herpesviruses through vaccination is to develop variants of the same virus that target specific populations.
“What we use for pediatric use to keep kids from getting infected might be different molecules than ones we give to adults who are already infected,” said Saphire. “Like the pediatric months might focus on preventing initial entry of the virus. For adults, you have to focus on finding and killing already infected cells.”
All of this work will be irrelevant if there’s no way to scale and provide equitable solutions because leaving the door open for any herpesvirus strain keeps the cycle turning and turning. That’s where ARPA comes back into play. Not only is the government agency providing the funds to drive this research, but the network of labs associated with ARPA has facilities to actually put all of this into play, whether it’s analyzing samples or producing vaccines.
America’s SHIELD will pursue vaccine development for various herpesviruses. That includes the highly contagious Epstein-Barr virus that causes mononucleosis, multiple sclerosis, and inflammation of the heart muscles and brain and is implicated in gastric cancer and multiple forms of lymphoma. America’s SHIELD will also look at CMV, which can cause devastating birth defects.
In the end, the $49 million pales compared to the $4 billion annual cost to the U.S. healthcare economy for birth defects caused by CMV, which is a little over 100 times what Saphire and her team have received for five years of research.
“If you can mitigate $4 billion using $49 million, that’s pretty good, and that’s what we want to do,” Saphire said. “And it’s an opportunity to help 90% of the nation just waiting around to see if they will get these leukemias and lymphomas.”
By just focusing on Epstein-Barr virus and CMV, the number of people’s lives America’s SHIELD has the potential to influence is astounding, and that’s without even taking into account highly prevalent herpesviruses, such as those of the sexually transmitted variety like herpes simplex virus type-1 (HSV-1) or type-2 (HSV-2).
Nevertheless, for all the strides that humans make in fighting off viruses, these “crafty little buggers,” as Saphire called them, will continue doing their research on us.
