The experiment was so elementary, and the results so surprising, that researchers working with San Diego’s Vical Inc. couldn’t really believe what they were seeing. It all seemed too simple.

They had been injecting submicroscopic fatty globules containing DNA or RNA into mice to see what would happen. The idea was that the fat globules, called liposomes, would be taken up by cells. The cells would use the genetic material inside to make proteins they couldn’t otherwise make.

The researchers found moderate success with that, but the rigors of science demanded that the experiment have a “control” portion--injecting the raw DNA or RNA into the mice to show that the liposomes themselves were making it possible for the new genes to be incorporated into the cell’s processes.

It turned out the cells like the raw material even better and began making the new proteins for as long as six months.

“This was a big surprise, and that’s really what you’re looking for in this area,” said [Dr. Philip Louis Felgner (born 1950)], director of product development at Vical. Felgner worked on the experiment with [Dr. Jon Asher Wolff (born 1956)] and others at the University of Wisconsin at Madison.

Researchers spent several months longer trying to find flaws in their methods or their conclusions. The literature of science is littered with examples of experimental results that deserved the label of too good to be true, explained [Dr. Karl Yoder Hostetler (born 1939)], vice president for research and development at Vical.

“We didn’t want any fiascoes,” he said.

Vical hopes that the results of this checking and double-checking, reported in today’s issue of the journal Science, will convert the company from a bare-bones start-up to a major player in the ranks of San Diego’s biotechnology community.

The company, which was founded in 1987, hopes to find financing to more than double its scientific staff of 22 as a result of the study. It is talking with several large drug companies to see if any would like to buy into the follow-up studies on the new gene transfer method, said Vical President Wick Goodspeed.

Some familiar names in San Diego science and business have played a role in Vical. Among them:

[Dr. Karl Yoder Hostetler (born 1939)], who is on leave from his longtime post as professor of medicine in residence at UC San Diego. His specialties include investigating ways to use lipid chemistry to improve the effectiveness of drugs.

[Dr. Douglas Daniel Richman (born 1943)], a founder and scientific adviser to the firm. Richman is a professor in residence of medicine and pathology at UCSD, specializing in virology and clinical trials of AIDS treatments.

[Dr. Dennis A. Carson (born 1936) ], also a scientific adviser to the firm. Carson recently resigned as head of the division of clinical immunology at Scripps Clinic to become head of UCSD’s new institute for research on aging.

Timothy Wollaeger, chairman of the board. Wollaeger formerly was senior vice president in charge of finance and administration for Hybritech Inc., the monoclonal antibody firm whose success was capped in 1986 with its $485-million acquisition by Eli Lilly & Co.

Howard E. (Ted) Greene, a director of Vical. He formerly was chief executive officer for Hybritech. Greene and Wollaeger were the driving forces behind Biovest Partners, a venture capital firm that financed several San Diego biotech firms.

W. Larry Respess, a Vical director. A leader in biotech patent law, he formerly was general counsel of Gen-Probe and Hybritech.

Until now, the best combination of science and business for Vical has been the multi-year research contract it received last summer from Burroughs Wellcome Co. to develop new forms of AZT for AIDS therapy. The study is investigating the idea that encasing AZT in fat globules would make it more powerful within the body.

The gene-insertion technique reported in Science this week is being suggested as a way to cause the body to generate proteins that would block persistent viral infections, ranging from AIDS to herpes. It also is seen as having potential use as a way to trigger cells to immunize the body against diseases, researchers say.

Vical is calling the new method “gene therapeutics,” to distinguish it from the traditional goal of gene therapy, which uses viruses to insert missing genes into the genetic codes of people with genetic diseases.

The so-called retroviral method has proved difficult and slow, despite several years of intense effort by research groups around the country, including a group led by Dr. Theodore Friedmann at UCSD.

Because retroviruses insert their own genetic code into the cells of their host, the method is also expected to be problematic as a gene therapy technique--since some scientists worry that this could harm the patient irreversibly in some unforeseen way.

Inserting the genes themselves into muscle cells--without any retroviral carrier--avoids this stumbling block entirely, [Dr. Philip Louis Felgner (born 1950)] said. The genes do their work of producing proteins, called expression, but they don’t seem to affect the cell’s own genetic structure, he said.

“People have worked in the gene therapy area for years assuming that a rather complex viral delivery system would be required in order to get expression. And we have found that you can do it very simply,” Felgner said.

It was the slowness of the gene therapy field that led Felgner’s collaborator, of the University of Wisconsin, to decide less than two years ago to get out of it altogether, Wolff said in a telephone interview.

Wolff was an assistant professor and a researcher in Friedmann’s UCSD lab before going to Wisconsin as an assistant professor of pediatrics and medical genetics in 1988.

“I had pretty much planned to get out of the gene therapy field because I got discouraged with the retroviral approach. Scientifically, it wasn’t very challenging,” he said. “Everybody was doing the same thing, and nothing was working that well.”

The results of the research contract with Vical, begun in January, 1989, have rekindled his enthusiasm, [Dr. Jon Asher Wolff (born 1956)] said.

He believes that, in the end, genetic therapies will involve a variety of techniques, not just the Vical method. But he and [Dr. Philip Louis Felgner (born 1950)] acknowledge that they expect some resistance to their ideas from the traditional gene therapy community.

“You’re talking about somebody who has spent his life in this field, and who would like to make the real breakthroughs that are going to allow it to be used in patients with diseases,” Felgner said. “There’s quite a bit at stake.”

Other collaborators with Wolff and Felgner on the research were [Dr. Robert Wallace Malone (born 1959)] of Vical and Phillip Williams, Wang Chong, Gyula Acsadi and Agnes Jani in Wisconsin.

Vical is planning to try to patent the technique, even though it involves no novel or complex steps unfamiliar to molecular biologists. In essence, it involves preparing DNA or RNA with standard techniques and then injecting it in the conventional way into muscle.

“The reason why we have patent position is that it was such a total surprise. Some of those things are the best patents you can get,” Felgner said. “Nobody who was ‘skilled in the art’ would have ever thought that what we have accomplished here was even possible. Nobody would have even thought to do the experiment.”

From South Africa to Brazil to California, the list of locations linked to new strains of the coronavirus is growing — and so are concerns that viral variants could undo the vaccine rollout.

The worries come at a time when most San Diegans still haven’t received a COVID-19 vaccine. That could change by the end of May, when President Joe Biden says there will be enough vaccine for all adults in the U.S. But by then, new and faster-spreading coronavirus strains will likely account for nearly all cases.

Does that mean this whole effort is for naught?

Not according to local researchers with a deep understanding of viruses and the immune system. They say there’s ample evidence that current vaccines work well against several of the well-known variants, and that immunity is never an all-or-nothing affair.

Manufacturers and federal regulators have signaled that updating current vaccines to keep pace with new strains will be relatively straightforward. Some of that work is already happening.

“On a one to 10 scale, my concern about variants is two or three,” said Dr. Mark Sawyer, an infectious disease expert at Rady Children’s Hospital who served on the panels that recommended that the Food and Drug Administration authorize the Moderna, Pfizer and Johnson & Johnson vaccines.

“I am worried about them. They could create problems — they could create big problems. But at the moment, based on what we know, they look like most of them are going to be manageable.”

Doses of the Pfizer-BioNTech COVID-19 vaccine at Rady Children’s Hospital. Recent studies suggest that Pfizer’s vaccine works well against a coronavirus strain first spotted in the U.K., though it may be less effective against one discovered in South Africa. But immunity is not all or nothing, and current vaccines are particularly effective at preventing severe disease and death from COVID-19.(K.C. Alfred / The San Diego Union-Tribune)

A dimmer, not a light switch

The emergence of new strains means the coronavirus is doing what all viruses do: mutating.

Each time a virus infects a cell, it copies its genetic material. But that’s not a perfect process. Given enough time, some copies will have a few random errors, or mutations — a bit like how you’re bound to make a few typos after transcribing the same document 20 times.

Most mutations don’t help a virus. Some might hurt it. But every now and then, a mutation lets a virus spread more easily from cell to cell or person to person. And viral variants with a competitive edge will eventually outnumber less successful strains.

It’s survival of the fittest, on a microscopic scale.

“Viruses are clever creatures,” said Dr. Douglas Richman, a UC San Diego virologist. “They accelerate Darwinian evolution.”

That’s why it was a matter of time before the coronavirus mutated in ways that made it more infectious. Many of the new variants have mutations that help the virus latch more tightly onto cells before slipping inside them. Others are less vulnerable to antibodies — Y-shaped proteins that can glom onto a virus’s surface and block infection.

But these mutations haven’t rendered vaccines useless.

One of the first variants to fuel fears was detected in the U.K last fall. The variant, also known as B.1.1.7, has since been spotted in San Diego, and researchers expect it to eventually account for nearly all COVID-19 cases in the county.

Scientists reported in late January that antibodies made by people who received the Pfizer vaccine blocked the U.K. variant and the original strain found in Wuhan, China, from infecting lab-grown cells about equally well. The same is true of Moderna’s vaccine.

By comparison, antibodies from people who’d gotten the Moderna and Pfizer vaccines were less effective against the so-called South Africa strain. That’s likely also the case for a strain first identified in Brazil, which shares several key mutations.

Real-world trial data from a different vaccine, made by pharma giant Johnson & Johnson, tell a similar story. The company’s vaccine was 72 percent effective in the U.S., compared to 66 percent and 57 percent in Latin America and South Africa, respectively.

It’s likely no accident the vaccine was less effective in regions where some of the more concerning variants are abundant, says Erica Ollmann Saphire, a researcher at La Jolla Immunology. But the findings also underscore an important point: Immunity isn’t black or white.

“The immune response is not really like a simple on-off light switch,” Saphire said. “It’s like a whole panel of dimmer switches. You have lots of options and lots of lights, and if one dims a little, the others might still be on.”

That’s because vaccines spark immune responses against many different regions of a virus, not a single spot, launching a salvo of antibodies to stop infection and an army of T cells to kill infected cells before they spew out more virus.

A diversified, multipronged attack makes it less likely that any one mutation (or several) will thwart an immune response.

“Most of those antibodies and most of those T cells are still going to work,” said Saphire, who leads an international effort to test more than 200 antibody therapies against various strains of the coronavirus.

Of all the recent reports, the most concerning to date found that AstraZeneca’s COVID-19 vaccine was 21 percent effective in a group of 2,000 South Africans — and just 10 percent against the fast-spreading viral strain first found in that nation.

But while the study prompted the South African government to stop its rollout of the AstraZeneca vaccine, the country simply pivoted to using doses from Johnson & Johnson.

It’s helpful to understand what vaccine “effectiveness” means when interpreting these numbers. When the FDA says that any coronavirus vaccine must be at least 50 percent effective, the agency is referring to how well the vaccine compares against placebos in preventing all COVID-19 symptoms — even a mild headache or a cough.

But keeping people alive and out of the hospitals is arguably the key to restoring some semblance of pre-pandemic normalcy. And by that measure, COVID-19 vaccines are highly effective: Not one person vaccinated in the Johnson & Johnson, AstraZeneca, Pfizer or Moderna trials has died of COVID-19.

“When I got my first shot, I got this incredible sense of relief knowing the data. I know that even if I get infected, it’s very unlikely I’ll get anything more than some mild symptoms,” said Richman, the UCSD virologist, who is 78.

“That beats death or being on a respirator by quite a bit.”

Dr. Douglas Richman, a UC San Diego virologist, was relieved to receive his coronavirus vaccine because he knew it would make him far less likely to develop severe disease. Richman is 78, and age is one of the strongest risk factors for COVID-19 hospitalization or death.(Jarrod Valliere / The San Diego Union-Tribune)

Tweaking and testing

While COVID-19 vaccine makers continue to dole out doses, they’re retooling their designs against viral variants.

Case in point: On Feb. 24, Moderna announced that it tweaked its vaccine to target the South Africa strain, with the National Institutes of Health set to begin testing the modified vaccine’s safety and ability to spark an immune response in a small clinical trial.

The FDA has indicated that it will be faster and easier for companies to adjust a vaccine that the agency has already authorized. The main requirement will be that antibody responses to the modified vaccine work as well against a new variant as antibodies to the earlier vaccine fared against the original strain.

Such studies could be done quickly on a hundred to a few hundred participants rather than by tracking tens of thousands of volunteers over several months.

“The approval doesn’t require these gigantic studies,” Richman said. “It just has to show that you get immune responses to the right (targets).”

Scientists update the flu vaccine each year. And like influenza, researchers expect the coronavirus to stick around — even once the vaccine rollout and public health precautions substantially slow the spread of the virus.

The current vaccines were developed and deployed in record time, less than a year after scientists discovered the coronavirus. That bodes well for scientists successfully updating the vaccine going forward. But Sawyer of Rady Children’s Hospital says there’s a simple way to get out in front of any future variants: Vaccinate as many people as possible, as quickly as possible.

“Then we’ll have less variants and won’t have to worry so much about California strains, South Africa strains, or whatever location you want to conjure up.”

Douglas Richman

Interview conducted by

Mark Jones, PhD

August 4, 1997

Douglas Richman

Dr. Douglas D. Richman, MD is Professor of Pathology and Medicine at the University of California, San Diego School of Medicine and Chief of the Virology Section, Professor and Director of the Research Center for AIDS and HIV Infection at the San Diego VA Medical Center. Dr. Richman has investigated HIV disease and pathogenesis for the past 20 years and was the first to identify HIV drug resistance. He is also a virologist and practicing physician with the Veterans Affairs San Diego Healthcare System. He has made major clinical and laboratory contributions to the field of HIV/AIDS, which represent a model of translational medical research. Dr. Richman helped design and conduct the clinical evaluation of new drugs and treatment strategies, including the first trial of combination antiretroviral therapy and the initial study documenting the value of the strategy of rendering HIV RNA undetectable. Two areas of his laboratory investigations represent landmark studies in HIV research. His laboratory first identified HIV drug resistance. He serves as a Consultant to the NIH, the Veterans Administration, the World Health Organization and the State of California. Dr. Richman has been Chairman and Member of Clinical and Scientific Advisory Board of Anadys Pharmaceuticals Inc. since December 2, 2004. He also serves as a Member of the HIV Scientific Advisory Board of Idenix Pharmaceuticals Inc. He serves as Member of Scientific Advisory Board at Biota Pharmaceuticals, Inc. He serves as Member of Clinical Advisory Board at Tobira Therapeutics, Inc., and Koronis Pharmaceuticals, Inc. Dr. Richman serves as Member of Clinical & Science Advisory Board of Presidio Pharmaceuticals, Inc. Dr. Richman serves as Member of the Advisory Board of Body Health Resources Corporation. He serves as Member of the Scientific Advisory Board for Multimeric Biotherapeutics, Inc., Chimerix Inc. and Monogram Biosciences Inc. He served as Member of the Scientific Advisory Board of GenPhar, Inc. He served as Member of Clinical Advisory Board of Achillion Pharmaceuticals, Inc. He was recently named to the endowed Florence Seeley Riford Chair for AIDS Research at UCSD. He serves on the Editorial Boards of numerous scientific journals, including the Journal of Virology and Antimicrobial Agents and Chemotherapy. He is a Member of the NIH AIDS Vaccine Research Committee. Dr. Richman has published more than 480 original research articles, reviews, and book chapters, and he is the senior editor of the major textbook of medical virology, Clinical Virology. He was honored with an NIH Merit Award and the Howard M. Temin Award for Clinical Science and Clinical Excellence in the Fight Against HIV/AIDS. Dr. Richman is a Fellow of the American Association for the Advancement of Science, the American Association of Physicians and the Infectious Disease Society of America. Dr. Richman trained in infectious diseases and medical virology at Stanford, the National Institutes of Health (NIH) and Harvard. He earned his B.A. degree from Dartmouth College, an M.D. degree from Stanford University and postdoctoral training at Harvard and the NIH.

Source: Bloomberg Businessweek

THE SAN DIEGO TECHNOLOGY ARCHIVE

INTERVIEWEE: Douglas Richman

INTERVIEWER: Mark Jones, PhD

DATE: August 4, 1997

• JONES: How long have you been here at UCSD? 1

• RICHMAN: Twenty-one years. 2

• JONES: When did you meet Karl Hostetler and Dennis Carson? 3

• RICHMAN: When I arrived, I became friends with them. Yeah, actually, one of the 4 guys I did a fellowship with at the NIH was a very close friend of Dennis', so I’ve 5 known them both since I got here. 6

• JONES: And you’ve collaborated closely with them over the years? 7

• RICHMAN: I’ve done research with them since the ‘70s, some collaborations, and 8 we’re friends as well. 9

• JONES: Were you working with Karl when he was working with calcitonin and 10 putting it in lipid envelopes? 11

• RICHMAN: He was doing some of that. We had worked with amantidine, an anti-12 influenza compound. We’d done some research for that, and then he was doing his 13 liposomal stuff and I was working on anti-virals. We decided to put it together. There 14 was a request for proposals for drug discovery programs at the NIH. We responded to 15 that, and my memory of it was that, although we both thought it was a good 16 proposal, the review committee decided to change the review criteria from what the 17 NIH requested proposal was, when they set up their criteria for evaluation. The 18 review criteria specified brain delivery, which had nothing to do with the NIH request 19 for proposals. So, we didn’t get funded, and we were both upset about that. Karl was 20 so ticked off that he said, ‘Well, I’m going to get private money to support it,’ and that was the start of, or at least part of the impetus of starting Vical. If we had gotten the 22 NIH grant, we might not have done it. 23

• JONES: Were you planning to be part of this from the beginning, or was it just Karl’s 24 idea for his stuff with calcitonin? 25

• RICHMAN: No, what prompted the Vical stuff, I think, was primarily the anti-viral 26 drug delivery. Calcitonin was sort of added on, I think, as part of the package. Karl 27 was sort of the major driving force. 28

• JONES: Do you recall how he got hooked up with Tim Wollaeger? 29

• RICHMAN: I think he just started snooping around for venture capital, to start 30 something. He can tell you more of how, in his snooping, he managed to. 31

• JONES: Then how did you get involved once... 32

• RICHMAN: Well, you know, we were scientific collaborators, and that’s been my 33 role, basically. I’ve sort of kept away from the business end. I’ve never fancied myself 34 as much of a businessman. I’m sort of a.... 35

• JONES: So, prior to this, you never had any notion of commercializing any of your 36 research? 37

• RICHMAN: No. 38

• JONES: When did you start working with AZT? 39

• RICHMAN: In the beginning, when it was actually the first...Sam Broder and I, we 40 were interns and residents together, and close friends. He was at the NCI at the time. 41 He subsequently became the director of the National Cancer Institute. But he was the 42 one who evaluated the drug under code for Burroughs-Wellcome, to show that it 43 worked against HIV. And he called me up to see the data, and discussed it with me 44 before it actually became public. And then they did the phase I study at the NCI, and 45 when it was clear that it had some activity, and that a large phase II study was 46 needed, I was asked to be one of the people to design the multi-center phase II trial. 47

• JONES: And when Vical was started, was the idea initially to develop something with 48 AZT? 49

• RICHMAN: Yeah, the delivery of necleosides in a more effective way was part of the 50 concept, yeah. 51

• JONES: Is this something that Vical was shopping before Burroughs-Wellcome? 52

• RICHMAN: No, clearly Burroughs-Wellcome had AZT. That was not an issue. But we 53 thought that we had a way that could potentially deliver it more effectively in a 54 modified form. And in fact, I guess the first business partner that Vical had was 55 Burroughs-Wellcome, to evaluate that. 56

• JONES: And were you involved in setting that up, did you go and make 57 presentations? 58

• RICHMAN: Yeah, yeah, I sort of made the initial contacts, and we went to RTP 59 [Research Triangle Park] and made presentations. 60

• JONES: So you knew people at Burroughs-Wellcome through your AZT research? 61

• RICHMAN: Well, even before that. David Barry who was head of Infectious Diseases, 62 and subsequently became president of Burroughs-Wellcome, we were fellows 63 together back at the NIH, and I’ve known him since the early ‘70s. 64

• JONES: So, they gave you, the company, $5 million. 65

• RICHMAN: I can’t remember the numbers. 66

• JONES: And you made it work, right? That was the outcome? 67

• RICHMAN: Well, basically, the ultimate development of that AZT derivative was 68 dropped by Burroughs-Wellcome. 69

• JONES: But you had delivered something to them that could have been developed 70 into a product. 71

• RICHMAN: Yeah, and for various reasons, they chose not to do it. 72

• JONES: So what was the fate of that technology? 73

• RICHMAN: Well, this is something that has had its ups and downs because there 74 were many other subsequent derivatives of this technology that have gone into a 75 whole series of patents that Karl has been the prime mover on, with applications for hepatitis and HIV, and those patents were...when Vical sort of discovered the naked 77 DNA technology, it was decided by the business leaders that they should keep the 78 business plan clean and focused, and they sold off all of the drug delivery component 79 to Nexstar, or whatever, it was a different name initially, and they were simply 80 incompetent in developing and managing that opportunity. They ultimately dropped 81 it and gave it back to Karl. 82

• JONES: So he owns it now? 83

• RICHMAN: Yeah. 84

• JONES: Is he trying to do something with it? 85

• RICHMAN: Yeah. 86

• JONES: But not with AZT, right? 87

• RICHMAN: Yeah, but actually Boehringer-Mannheim is doing something with AZT 88 that, in fact, ended up being covered by one of these patents. 89

• JONES: So they’re now licensing it? 90

• RICHMAN: Well, I think they had to license it, yeah. Karl can tell you the details. 91

• JONES: Well, after the drug delivery component was sold off, did that effectively end 92 your participation in the company? 93

• RICHMAN: No, when that was discovered, we had scientific advisory board meetings 94 to discuss what to do. And I suggested that the best way to prove that this was 95 effective was to show that you could immunize animals and protect them from dying. 96 Prevention of death was the most convincing. And so I suggested that the influenza 97 model would be the best way to do it. And actually I generated the reagents and the 98 various constructs and viruses and models from various colleagues that I knew from 99 when I was in influenza research, and assembled them, brought them to Vical, and 100 designed the experiments that ultimately proved that the naked DNA protected mice. 101 They sold that to Merck and in its various configurations, I was basically dropped 102 from even the conception. You know, it was published without my name even being 103 acknowledged, that Science paper that showed that it worked, and my comments to 104 them about how they had performed and various other things probably led them to choose to drop me, as well as Dennis Carson, from the Scientific Advisory Board. So, 106 my history as a co-founder- that was the end of it. 107

• JONES: That was something that you decided not to challenge? 108

• RICHMAN: I told them what I thought of them and just left. I have work to do. I’m 109 an academic. 110

• JONES: Early on, were you involved in recruiting people to Vical? 111

• RICHMAN: Yeah, I was involved in evaluating people like Danny King and Wick 112 Goodspeed, and various other people who were hired. I was involved in interviewing 113 them and talking to them. 114

• JONES: And scientific people as well? 115

• RICHMAN: Yeah, Phil Felgner, for example, right. So, early on, I was sort of more 116 involved. I was actually on the Board for the first several months or whatever, but as 117 venture capital came in, the venture capitalists took board positions. 118

• JONES: Have you been involved in other companies locally, or elsewhere? 119

• RICHMAN: I’ve been a consultant on scientific advisory boards for a number of 120 companies. 121

• JONES: Nexstar? 122

• RICHMAN: No. Initially, Viagene. I’m on the board of company up in the Bay Area, 123 Virologics, and then I’m involved with Triangle, which Karl and Dennis founded. 124

• JONES: What were the connections with Viagene? 125

• RICHMAN: That’s sort of a gene therapy company, and they wanted to get into HIV, 126 so they wanted somebody who knew something about HIV. 127

• JONES: Who contacted you? 128

• RICHMAN: Doug Jolly. 129

• JONES: Did you know him when he was here? 130

• RICHMAN: A little bit. 131

• JONES: But mostly by reputation? 132

• RICHMAN: Yeah, I guess so. 133

• JONES: Are you involved with Dynavax? 134

• RICHMAN: I’m on their SAB as well, because I’ve been working closely with Dennis 135 and [?]. We have a paper in this month’s Nature Medicine. 136

• JONES: What was your impression when Vical started, you were aware of Hybritech? 137

• RICHMAN: Yeah, actually Ivor and Sam Broder and I were all interns and residents 138 together at Stanford, twenty-seven, eight years ago, and his lab was right next to mine 139 at the VA. 140

• JONES: Did you ever collaborate with him? 141

• RICHMAN: I never did any research collaboration, but I knew what they were doing, 142 and I knew Howard Birndorf, his lab tech in the lab next door at the VA on the sixth 143 floor. 144

• JONES: What was your impression of the Hybritech people and what was going on? 145

• RICHMAN: It struck me as more entrepreneurial than science, but, you know, that’s 146 fine, I’ve got my work to do. 147

END INTERVIEW