AIDS viruses lying dormant in human cells can probably be activated by any of a wide variety of other infections, some of them minor, scientists reported yesterday.

The concept that other infections can activate a case of the deadly acquired immune deficiency syndrome has been put forward by several scientific groups. The new report strengthens the evidence for this concept and establishes a mechanism by which the AIDS virus forces the invaded cell to produce more virus copies.

The virus attacks T-lymphocytes, or T-cells, important cells of the immune defense system. The scientists identified a specific protein of T-cells, NF kappa B, that the AIDS virus subverts to help make the infected cell produce more AIDS viruses.

But in uninfected cells, NF kappa B appears to play a role in the activiation of the T-cells against almost any new infection.

Thus, activiation of an AIDS-infected cell in response to the appearance in the body of a different invader might force that cell to produce new AIDS virus particles.

One of the major problems in attacking AIDS with antiviral drugs is the fact that the virus can invade T-cells and remain inside them - inactive and virtually undetectable - for substantial periods of time. Conceivably a drug designed to inactivate the protein could do so without disrupting the T-cells' vital defensive functions, but this remains to be proved.

The ability of the AIDS virus to ambush the body's immune defenses by lying dormant in cells is a major worry among scientists who are attempting to design effective vaccines against the disease. The new evidence suggests the possibility that immunization itself might activate T-cells already infected with the AIDS virus in cases in which the patient was not known to be infected.

''Invasion by viral, bacterial and protozoan organisms in patients would therefore pose a risk beyond the immediate infection said Dr. Gary Nabel and Dr. David Baltimore, both of the Whitehead Institute for Biomedical Research in Cambridge, Mass., in their report in the issue of Nature published today. The protozoa include important disease causing parasites such as those of malaria. .

The specific role of the NF kappa B in T-cell activation is still unknown. The normal functions of T-cells include production of substances important to the immune defense system such as Interleukin 2 and gamma interferon.

Dr. Nabel said a drug that would block the action or the production of the NF kappa B protein might prevent T-cell activation. If it did, patients might be helped by giving them regular doses of some of the T-cell products to replace those the cells would have made. 

Executive Summary : VICAL [, aka Vical Incorporated], ) PROPOSED IPO PROCEEDS ESTIMATED AT $17 MIL., at an assumed offering price of $9.25 per share, or roughly $19.6 mil. if the 300,000 share overallotment option is exercised fully. The San Diego-based gene therapy firm filed a revised registration statement with the Securities & Exchange Commission for a 2 mil. share initial public offering July 2. Underwriters are Hambrecht & Quist and Vector Securities. Vical has been seeking to go public since January. However, in the continuing difficult market for biotech stocks, the company has been forced to scale back its offering from the 3.45 mil. shares proposed earlier this year. Vical now expects to net roughly $10 mil. less than the $27.3 mil. it previously estimated ("The Pink Sheet" Jan. 18, p. 20). Vical plans to use "substantially all" of the net proceeds for research and development costs. The company expects proceeds plus existing cash to cover expenses through mid-1995, the IPO prospectus states. In April, Vical received a $1.25 mil. payment from Merck in exchange for the extension through 1994 of a licensing option on preventative vaccines for herpes simplex, hepatitis B and C, human papilloma virus and measles developed using Vical's technology. Merck and Vical entered into a collaboration in preventative vaccines in May 1991; Merck currently has rights to preventative vaccines developed for influenza and for HIV ("The Pink Sheet" June 17, 1991, In Brief). A gene-based cancer therapy being developed by [Dr. Gary Jan Nabel (born 1953)], University of Michigan in collaboration with Vical is currently in Phase I/II trials. The collaboration was formed in November 1992. The treatment, which employs a DNA/liposome complex encoding a histocompatability antigen (HLA-B7), was approved for a second trial by NIH's Recombinant DNA Drugs Advisory Committee at its June 7-8 meeting and now awaits FDA approval ("The Pink Sheet" June 14, p. 6). Vical plans to file an IND for an in-house Phase I/II study of the treatment. Two treatments that involve the intramuscular injection of genes encoding cytokines -- interleukin-2 and transforming growth factor-beta -- are currently in preclinical development under an agreement between Vical and Dennis Carson, MD, University of California-San Diego. Other areas Vical is pursuing using its direct gene targeting technology include therapeutic vaccines (targeted indications are AIDS, hepatitis B and herpes), the treatment of cardiovascular disease, specifically targeting ischemic heart disease with fibroblast growth factor-5, and the treatment of hemophilia A and B through the production of Factor VIII and Factor IX, respectively. Vical has fairly strong cash reserves in the event that the IPO is further delayed. As of March 31, the company had about $19.2 mil. in cash and cash equivalents. The biotech firm had $10 mil. at the end of 1992. Research and development costs rose to $4.4 mil. in 1992, compared to $3.6 mil. in in 1991. The firm has gained the bulk of its revenue so far this year from a sale of technology: Vical received net proceeds of $3.1 mil. in 1993, in addition to a payment of $1 mil. in 1992 from Vestar in an agreement that transferred rights to Vical's lipid prodrug technology to Vestar. 

With a "pop" that sounded like the opening of a soft drink can, a tiny amount of an experimental HIV vaccine was injected with a needle-less device Friday morning into the arm of a healthy 58-year-old California man at the National Institutes of Health (NIH).

"It didn't hurt at all," he said in an interview later. "The shots that I've had for dental work are much worse."

Known as VRC-001-VP, this vaccine is not the first one targeting HIV to be tested in a clinical trial. In fact, more than three dozen other HIV vaccines are under study in humans.

But the Friday morning vaccination is nonetheless significant for what it represents: the first step in an ambitious, well-funded U.S. effort to create vaccines against some of the deadliest diseases.

"It's a beginning salvo that signals a whole series of things coming down the pipeline" from NIH, said Barton Haynes, director of the Human Vaccine Institute at Duke University in Durham, N.C.

Opened a year ago, the sleek, $34 million Dale and Betty Bumpers Vaccine Research Center (VRC), located on the NIH campus in Bethesda, is the first federal facility devoted entirely to vaccine research and production. (The center is named for the former U.S. senator from Arkansas and his wife, who are staunch advocates of immunization.) By integrating qualities of a private biotech company, a major academic institution and a federal agency, the center is designed to streamline development of lifesaving vaccines. Research, development and even some production will occur under its roof.

"I don't believe that there is any other facility like it," says Dani Bolognesi, one of the pioneers in AIDS vaccine research and now CEO of Trimeris, a biotech company in Durham. "The importance is that you have all of this in one place."

The center also is the nexus of collaborations among NIH, other federal agencies and private companies. The final touches on the inaugural HIV vaccine, for instance, were done by Vical, a San Diego biotech firm. But once the VRC goes into full production, it will also manufacture vaccine and collaborate with a military facility at Fort Detrick in Frederick, Md.

In short, VRC scientists will be able to conceive, develop and produce new vaccines rather than negotiate licensing agreements with drug companies, a procedure that can tie up products for years. This first product was developed in less than a year by the VRC's director, Gary Nabel, and two research fellows -- Yue Huang and Wing-Pui Kong.

"This place fills a niche not filled by universities or private industry," says Barney Graham, chief of the VRC's clinical trials and viral pathogenesis laboratory, who left a tenured position at Vanderbilt University in Nashville to join the center earlier this year. "We have resources that a university doesn't have and flexibility that industry doesn't have." AIDS -- now spreading rapidly throughout the world, claiming 7,000 lives and infecting 15,000 people every day -- is the center's first target and "the most challenging epidemic that we have faced in our lifetimes," Nabel says. HIV is such a difficult target because it constantly changes within each infected individual.

But HIV is just the beginning of VRC's efforts. The process established to produce HIV vaccines will launch a production line to tackle other diseases, including Ebola virus, malaria and tuberculosis, although it will be at least several more years before these products go into clinical trials.

With heightened concerns that terrorists might spread deadly diseases, "now, more than ever, we realize that we can contribute not just to personal health, but to public health, whether these are natural outbreaks or man-made," Nabel says, noting that anthrax could be one of those targets down the line.

Nabel even envisions the center eventually working on products to prevent more chronic, common illnesses that are thought to be caused by infectious agents, including Alzheimer's disease, arthritis, heart disease and autoimmune disorders such as lupus and multiple sclerosis.

But even state-of-the-art labs, $40 million in funding for 2002 and recruitment of respected researchers can't do it all. The effort requires a steady supply of something that can be more difficult to find: volunteers willing to be injected with experimental vaccines.

Such people haven't been easy to find in the Washington area. Graham hopes to overcome that with more community outreach to explain what the VRC does and to underscore the need for healthy volunteers. "We have to be able to recruit more people locally," he says.

For now, however, the first HIV vaccine volunteer has traveled across the country to participate. He is tall, with a sonorous voice and the golden glow of someone who lives in California, although in his case, it's northern California. His silver hair is set off nicely by a dark gray T-shirt.

As the center's first volunteer, he is being closely observed by the medical staff, who regularly take his blood pressure and other vital signs.

"We didn't seem to leave any time for bathroom breaks," he jokes.

The volunteer is also being carefully guarded by Graham, who agreed to arrange an interview only with the stipulation that the volunteer's name not be disclosed.

A bright yellow bandage covers an IV needle in the volunteer's right forearm as he sits in an eighth-floor conference at the NIH Clinical Center, talking about his decision to participate. For this first trial, the institutional review board -- the body that monitors all clinical trials at NIH -- has required that an intravenous needle be inserted, allowing medicines to be administered quickly if there should be an allergic reaction to the vaccine.

The volunteer rolls up the sleeve on his left shoulder to show the slightly red, nickel-size spot where the experimental vaccine was injected with a needle-less Bioject device.

Newspaper ads, including some in The Washington Post, regularly recruit for healthy study participants. For this year-long HIV study, 21 volunteers will be enrolled. As the VRC becomes fully operational, up to half a dozen vaccine trials will be run simultaneously, each involving about two dozen volunteers. The hope is that many study subjects will come from the Washington area, although recruitment here has traditionally been spotty.

This volunteer learned about the clinical trial from his next-door neighbor in Sacramento and called NIH last spring to find out how to participate.

That led to an hour-long telephone interview, followed by a trip to NIH for a physical exam and blood and urine tests. Participants must be healthy, between the ages of 18 and 60 and not infected with HIV.

The volunteer didn't expect to be the first subject in the study. In fact, he thought there would be so many participants that he might not even make the study. "It really makes no difference to me whether I am first or last, as long as I can contribute in some way," he says -- although he quickly worries aloud that those words will make him seem too altruistic.

Often participants in clinical trials are motivated to help because they have a family member or loved one with the disease. Not so for this volunteer, although he does have one friend who is HIV-positive.

The volunteer has spent his life working with developmentally disabled children as a teacher and a speech therapist, and he now works in special education for the State of California. He's also writing a book about reciprocity -- a value he that he believe feels helped to build the United States, but is often missing these days.

"If I am going to walk the walk and talk the talk, I need to be involved," says the volunteer, who will make 14 visits to NIH during the study. Travel expenses are also covered by the trial -- which is part of the reason the VRC would like to find local participants.

"I have been fortunate," the volunteer says. "I went from poverty to having a nice home and children and a good job and felt that this was my way to give back to society. I just have a real, true, honest belief that we act in a reciprocal nature in our society. This is my way of doing that. It comes from my heart."

And yes, he expressed a few last-minute reservations and a little nervousness before he was injected with the vaccine, although he knows that there is no risk of contracting HIV. "It wasn't [a] strong [feeling]," he says. "I didn't break out in a sweat or anything like that."

What sustained him are the grim numbers of AIDS. "Fifteen thousand people are being diagnosed per day as HIV-positive," he says. "I am one life. I am very happy to let them use me, although 'use' is not exactly the right word. If I can help, I would be very happy. I don't think . . . I am wonderful for doing this. It is just an aspect of giving in our society. It was a chance that was provided for me to do something."

What this trial will do is determine the safety of this particular vaccine in humans. VRC-001-VP is a DNA vaccine -- one of five such products now under study out of nearly three dozen different AIDS vaccines. (DNA vaccines contain genetically re-engineered snippets of a disease's DNA.)

No one expects any one of these vaccines to be the final answer for AIDS. They are merely incremental steps in an ongoing process likely to take another decade before producing an effective vaccine, researchers say.

Studies suggest that it will take at least a one-two punch to thwart HIV. That will mean developing a vaccine that can boost cellular immunity provided by white blood cells and humoral immunity, production of the antibodies that attach to invaders and target them for destruction by the immune system.

"Antibodies neutralize the virus, prevent new infection and activate the inflammatory response from white blood cells," Nabel explains. White blood cells target HIV-infected cells and may halt virus production.

But HIV is so crafty that antibodies can't always recognize it. "The amount of variation that occurs each year worldwide with influenza is what happens to just one infected person with AIDS," Nabel says. "It is mind-boggling how much of a moving target HIV is."

The HIV virus has been just as wily at outsmarting white blood cells, too, which are designed to destroy it. "HIV hides its vulnerable surface structure, much like a bioterrorist," Nabel says.

So HIV vaccine researchers are simultaneously looking at multiple vaccines to find the most effective combination approach to tackle HIV on both fronts. The study of VRC-001-VP will also provide valuable information about how quickly the immune system responds to the vaccine. "The questions they are asking . . . for example, the timing of the second and the third doses, that's information that will quickly be incorporated into other studies," says Duke University's Haynes.

The beauty of the VRC is that "we don't have to wait for grant cycles, we're not operating on a profit margin or interested in protecting our intellectual property," Nabel says. "We're working toward scientific principles."

And that gives them the unprecedented ability to move fast. "To have taken this vaccine from concept to clinical-grade product in such a short time is an extraordinary accomplishment," says Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases, which oversees the vaccine center.

If there's one thing that pandemics from AIDS to influenza have taught researchers, it is the importance of moving fast and being proactive.

"That, to me, is the lesson of AIDS," Nabel says. "We need to be able to respond earlier and get to the problem before if permeates the population."

The first dose of an experimental HIV vaccine, above, was administered Friday as a government campaign to develop disease prevention products got underway.Gary Nabel, seated, directs the new Vaccine Research Center at NIH, which has started testing an HIV vaccine. The center's staff includes researcher Yue Huang, left, and Barney Graham, chief of the clinical trials laboratory.

A team of scientists has discovered how the deadly Ebola virus hijacks human cells, opening potential avenues to new drugs and a vaccine.

Ebola kills roughly 80% of those who contract it, usually causing them to bleed to death in a few weeks. Since its discovery in 1976, the virus has killed 1,000 people, according to the World Health Organization. Recent Ebola outbreaks in the Republic of Congo and neighboring Gabon in central Africa have killed several dozen people. The virus's mysterious appearances, rapid course and lack of treatment have made it a daunting challenge for public health -- and a potential weapon for terrorists.

Now, a research team says it has answered important basic questions about how Ebola, and a related virus, Marburg, commandeer human cells. Their findings shed light on possible ways to design drug therapies. The Ebola virus, shaped like a shepherd's crook, targets tiny fat platforms called "lipid rafts" that float atop the membrane of human cells. These cholesterol-rich rafts are the viruses' gateway into cells, the assembly platform for making new virus particles, and the exit point where new virus particles bud.

This virus-like particle, the harmless hollow shell of the Ebola virus, may one day be useful in creating an Ebola vaccine. The particle has been disarmed of its genetic material and is unable to replicate.

The team's report, set to be published Monday in the Journal of Experimental Medicine, "is highly significant," says Eric Freed, principal investigator in the laboratory of molecular microbiology at the National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health in Bethesda, Md. "It adds another human pathogen to the growing list of viruses that use lipid rafts."

The findings add new insight into the life cycle of viruses and how they subvert human cellular mechanisms. It is a critical early step toward one day creating drugs that would stop viruses from replicating. Ebola and Marburg, both members of a family of hemorrhagic-fever viruses called filoviruses, share the reproduction strategy of viruses ranging from measles and influenza to HIV, which causes AIDS. Their ability to traffic aboard lipid rafts may help them evade the human immune system, researchers speculate.

One of the researchers, [Sina A Bavari (born 1959)], at the U.S. Army Medical Research Institute of Infectious Diseases in Fort Detrick, Md., says, "By understanding how Ebola and Marburg are entering into and budding from the cells, it gives us an avenue to come up with new therapeutics that would alter these pathways." Dr. Bavari's co-author is M. Javad Aman, of Clinical Research Management Inc. in Frederick, Md.

The push to probe Ebola has assumed greater urgency since the Sept. 11 terror attacks, as fears have grown about the existence of weaponized forms of Ebola or Marburg. Such bioterror weapons were in development within the former Soviet Union, according to Kenneth Alibek, a Soviet bioweapons scientist who defected to the U.S. and wrote the 1999 book "Biohazard."

Says [Sina A Bavari (born 1959)], "It doesn't take a Nobel laureate to figure out that something so deadly could be transformed into a bioterror agent." Yet-to-be-developed vaccines and antiviral drugs could be critical elements of bioterror defense against the viruses.

Because their targets, the lipid rafts, are made of fat, known agents such as the popular cholesterol-lowering statin drugs may offer one possible model for new drug therapies. Antifungal drugs, such as nystatin and filipin, that break up fat could be other possible models.

In their research, [Sina A Bavari (born 1959)] and [Drs.] Aman produced harmless copies of the Ebola virus that, it turns out, may be a possible vaccine candidate. The virus-like particles, known as VLPs, are hollow protein shells, gutted of their virulent genome. The researchers say the hollow proteins could elicit an immune defense, because they signal the body that an Ebola invasion is under way without actually causing disease.

"You're basically fooling the body," [Sina A Bavari (born 1959)] says, "but the virus cannot replicate itself." The hollow-protein model is one approach being used in the search for a vaccine for HIV. Future studies will examine whether such a strategy is safe and effective against Ebola and Marburg, he adds.

The researchers say their creation of the hollow VLPs could allow Ebola research to take place more freely in laboratories across the country, on regular lab benches outfitted with suction hoods, to prevent the escape of particles. At present, scientists have to wear space suits and work behind air-locked doors in high-containment Biosafety Level 4 labs when handling live Ebola virus.

Another National Institutes of Health researcher working on Ebola, [Dr. Gary Jan Nabel (born 1953)], of the Vaccine Research Center at NIAID, applauds the report. Dr. Nabel has published studies showing that Ebola vaccine created using experimental "naked DNA" -- the opposite of the hollow VLPs, in a way -- protected monkeys against lethal Ebola infection when given with a booster shot of the vaccine. His team is partnering with [ Vical Incorporated], a San Diego biotech company, to produce the vaccine prior to launching studies of its safety in humans.

"People are waiting with bated breath for a drug or vaccine," [Dr. Gary Jan Nabel (born 1953)] said. "These [studies] show that we're on the road that will get us there."

The first test in humans of an experimental vaccine against the deadly Ebola virus began yesterday, government scientists said.

The vaccine, administered by injection, was designed to try to prevent outbreaks of the lethal hemorrhagic fever where it occurs naturally in Africa. It is also a bid to thwart any efforts to use the highly infectious virus as a bioterrorist agent.

As part of a standard three-stage process, the first phase involves testing the vaccine's safety. Scientists also plan to measure immune responses among volunteers receiving the shots.

No effective treatment exists against the viral infection, which kills up to 90 percent of victims quickly from severe internal bleeding. Ebola was discovered in 1976 in the Republic of Congo, then Zaire. This week, the World Health Organization reported a new outbreak of Ebola in that country, attributing 11 deaths in as many cases to it.

The experimental DNA vaccine is synthesized using modified, inactivated genes from the Ebola virus. Because it does not contain any infectious material from the virus, recipients cannot get the disease, said [Dr. Gary Jan Nabel (born 1953)], who directs the institute's Vaccine Research Center.

Researchers plan to test the vaccine on 27 people, ages 18 to 44. They are expected to receive three injections of either the experimental vaccine or a placebo at the National Institute of Allergy and Infectious Diseases in Bethesda, Md., over two months. They will then be monitored for a year.

The first volunteer, Steve Rucker, a 36-year-old research nurse at the institute, said in a phone interview that he felt fine after the vaccine was injected in his left arm yesterday.

Mr. Rucker, of College Park, Md., said he was participating because he believed that the findings from animal tests were ''extremely promising.''

[Dr. Gary Jan Nabel (born 1953)] said in a telephone interview that only a handful of individuals, mostly institute employees, had volunteered for the study and that his team needed at least 20 more volunteers. Details are posted at www.clinicaltrials.gov.

The vaccine is made by [Vical Incorporated], a biotechnology company in San Diego that has collaborated with [Dr. Gary Jan Nabel (born 1953)]'s team as they tested the vaccine on animals.

The goal is to use the Vical vaccine and another one to protect against Ebola in a prime-boost strategy. Under those conditions, the Vical vaccine would be given first to prime the immune system. Then a different vaccine, which uses an adenovirus (that causes colds) would bolster the immune system that had been primed by the Vical vaccine. The second vaccine is still being developed for human use; the first tests in volunteers are expected to begin next year, Dr. Nabel said.

Tests of the prime-boost strategy are expected to begin in 2005. But the schedule depends in part on the findings from the current tests.

Of the volunteers in the Vical study, 21 will get injections of the vaccine and 6 a placebo. Neither the volunteers nor the scientists will know which volunteers received which type of injection until the scientists analyze the results.

The government's program to defend against bioterrorism has helped accelerate development of a vaccine, said Dr. Anthony S. Fauci, the institute's director. ''An effective Ebola vaccine not only would provide a life-saving advance in countries where the disease occurs naturally, it also would provide a medical tool to discourage the use of Ebola virus as an agent of bioterrorism,'' he said.

The human study is based on animal experiments in which Dr. Nabel's team gave the two vaccines separately to guinea pigs and monkeys. When the researchers exposed the animals to Ebola virus, they found 100 percent protection, Dr. Nabel said.

A single injection of the adenovirus vaccine provided faster protection than expected.

Because it is unethical to deliberately expose humans vaccinated against Ebola to the virus because the disease is so lethal, scientists and government officials might have to apply what they call ''the two-animal rule.'' Government officials recently adopted the rule for possible licensing of a vaccine that proves safe in humans and shows adequate protection against a deliberate infection in two species of animals.

[Dr. Gary Jan Nabel (born 1953)] said he envisioned that health workers might someday vaccinate against Ebola the same way epidemiologists used the smallpox vaccine to eradicate that disease. The strategy involved vaccinating all possible contacts of the initial cases and then their contacts as well.

Scientists might test the vaccine in an outbreak of Ebola under emergency conditions.

Scientists trying to develop vaccines against Africa's deadly Marburg and Ebola viruses are reporting an important milestone, a new type of vaccine that prevents the diseases in monkeys. Successfully immunizing monkeys is an essential step toward producing human vaccines.

Two new vaccines, one for Marburg and one for Ebola, were 100 percent effective in a study of 12 macaques being published today in the journal Nature Medicine. Monkeys given just one shot of vaccine and later injected with a high dose of virus did not even get sick. Normally, all the animals would be expected to die.

The Marburg and Ebola viruses are closely related, and in both people and monkeys they cause hemorrhagic fevers that can be fatal within a week. There is no vaccine or treatment for either disease. Death rates in people can be high, sometimes exceeding 80 or 90 percent.

Angola, where a Marburg epidemic was first detected in March, is still struggling to contain the disease, which has killed 340 of 408 victims. The virus is spread by contact with blood, saliva, vomit or other fluids from sick patients.

The two new vaccines are still experimental, and will not be ready to be tested in people for at least two years. If human trials are successful, products might be ready for licensing five or six years from now, the researchers said. The vaccines would not be used for routine immunization, but would be given to health workers in high risk areas, virus researchers and people who had been exposed to the disease, such as relatives and others in close contact with sick patients. Eventually, it might be possible to combine the vaccines to protect people from both diseases with a single shot.

The new vaccines are not the first to protect monkeys. An earlier one, first proved in 2003, may go into safety studies in people in the United States later this year. Each vaccine has its advocates, and researchers say it is advantageous to have several candidates on the horizon.

The work described in Nature Medicine today was done by scientists from the United States and Canada, led by Dr. Steven M. Jones and Dr. Heinz Feldmann of the Public Health Agency of Canada in Winnipeg, and Dr. Thomas W. Geisbert of the United States Army Medical Research Institute of Infectious Diseases in Fort Detrick, Md.

Dr. Jones said the goal of the research was to provide a vaccine that could be used to stop outbreaks like the one in Angola or to protect people from germ warfare. He and other researchers said that governments and the military developed a strong interest in making vaccines against Ebola and Marburg during the 1990's after a Soviet defector said that Russians had stockpiled the Marburg virus, weaponized it and packed it into warheads for possible use in attacks on cities or battlefields.

"Marburg and Ebola are not as significant threats as smallpox would be, but one could wreak incredible human health tragedies in this country and could probably create a huge economic burden even if the diseases didn't spread like wildfire," said Dr. Peter B. Jahrling, an author of the article and an expert on viruses and bioterrorism who used to work for the Department of Defense and is now a chief scientist at the National Institute of Allergy and Infectious Diseases, of the National Institutes of Health. "But I think a lot of people here also see the humanitarian aspects of providing vaccine to people who need it."

Dr. Cathy Roth, head of the emerging and dangerous pathogen team at the World Health Organization, said: "This work is very interesting, very exciting and very promising. There's a long way to go before this vaccine could be put into people. But we really do hope it is pursued."

To make the vaccine, the scientists used another virus, V.S.V., for vesicular stomatitis virus, which causes a mouth disease in cattle but rarely infects people. They chose it because it has a similar genetic structure to the Marburg and Ebola viruses, and because other researchers have had success with it in developing vaccines.

They altered V.S.V. by removing one of its genes -- the change makes it harmless -- and replacing it with a gene from either the Marburg or Ebola virus. The transplanted gene forced V.S.V. to produce Marburg or Ebola proteins on its surface. The proteins cannot cause illness, but they provoked an immune response that protected the animals.

The monkeys were housed at a high-level biohazard laboratory at Fort Detrick, where the researchers, wearing space suits, watched them intently for signs of illness after they were injected with Marburg or Ebola.

"By Day 6, I have a very good idea of whether it's going to work or not," Dr. Geisbert said. "On Day 6 I was feeling really good. By the time we get to Day 10, if the animals haven't become sick or had any problems, we pretty much know it's worked. It is an incredibly good feeling. All the people on the team are high-fiving. I was communicating with Heinz and Steven every day, two and three times a day. 'How are the monkeys? How are the monkeys?"'

As the team pursues its research, other scientists are moving ahead with the previously developed Ebola vaccine, based on an inactivated version of another type of virus, an adenovirus, which can cause common cold symptoms in people. That vaccine, tested in 2003, also protected monkeys, and studies in people may begin this year.

Dr. Jahrling, who has worked on both types of vaccine, said the government was paying for both approaches to cover its bets. He said he thought a vaccine based on an adenovirus would be ready before one based on V.S.V.

"They've got a runner on third with that one," he said, "and the other guys have a runner on first."

Dr. Jahrling added: "A little competition is good. It accelerates everybody. If nobody's behind them they kind of slow up."

But Dr. Gary Nabel, head of the Vaccine Research Center at the N.I.H. infectious disease institute, who has been working on the adenovirus vaccine, said: "I don't look at it as a race. For me, the adversary is the virus and whatever gives us the best opportunity to defeat the virus is what we need to go with."

The flu season has gotten off to a late start, allowing people more time to get the annual vaccine before the season's inevitable peak.

But the nation's health authorities and a few scientists in the forefront of vaccine technology say we could be just a year from human trials of a "universal flu shot" that would make the annually reformulated ones obsolete.

Ideally, this universal shot would catch all previous versions of the ever-morphing flu virus, as well as future mutations.

It would take the guesswork out of calculating the shot Americans are urged to get every winter - averting missteps like the one that left the public vulnerable to the swine flu pandemic of 2009- 10 that affected as many as 89 million people.

If trials continue to go as they have at Philadelphia-based [Inovio Pharmaceuticals, Incorporated], officials there say a shot could be available to the public in five years.

Even if those trials fail, national vaccine experts such as [Dr. Gary Jan Nabel (born 1953)] at the National Institutes of Health are hopeful that scientists will succeed in making a shot that works before the decade is out.

"If you went back five years, you would've said then, 'How would we ever get there from where we are?' Now we're all more optimistic, whether it be Inovio or someone else that succeeds," said Nabel, director of the Vaccine Research Center at the National Institute of Allergy and Infectious Diseases.

Inovio's $3.1 million grant from the NIH is just one of several helping researchers pursue this previously unthinkable possibility. Another grant has gone to The Scripps Research Institute, which has labs in Jupiter and in La Jolla, Calif.

What changed? Technology, and our understanding of how we can neutralize viruses, scientists say.

Nabel cited research, including that at Scripps, that dates back three or four years and pointed the way to how building this one-shot-kills-all vaccine might work.

Shots involve guess work

Until now, doctors have tackled the flu with methods that date back at least 50 years.

Vaccines deliver a decoy, in this case a dead or weakened version of the influenza virus, to stimulate a person's immune system. In other words: Attack what looks like this.

But the flu virus is a master at defense, dressing itself with an outer envelope that can mutate in months. And there are thousands of varieties of influenza, so health authorities each year pick a few they think are most likely to cause the most problems.

"They get together in January or February and look at what's going on in the Southern Hemisphere," said [Dr. Jong Joseph Kim (born 1969)], Inovio's CEO. "They're looking a season ahead and trying to find three strains from thousands of varieties out there.

"They do their best, and they actually have a pretty good success rate."

But when they don't, the consequences are dire.

"We all saw what happened in 2009 with the H1N1 (swine flu) outbreak," the NIH's [Dr. Gary Jan Nabel (born 1953)] said. "There's a great example of where we were all preparing for one type of seasonal flu, and something came in and it was a complete wild card."

"We were caught flat-footed," he added. "There were deaths that could've been prevented if we had a universal vaccine."

The U.S. Centers for Disease Control and Prevention estimates between 8,870 and 18,300 Americans died of swine flu-related causes from April 2009 to April 2010.

[...]

Finding common aspects

It has been known for years that flu viruses could mutate in thousands of ways, but only recently were researchers - including those at Scripps and [Inovio Pharmaceuticals, Incorporated] - able to begin identifying what made them the same, finding antibodies that targeted those parts and understanding how they work.

"We looked at flu viruses for the last 100 years," Inovio's [Dr. Jong Joseph Kim (born 1969)] said. "Because of DNA sequencing, we have a very good database of what strains have been affecting humans."

While there were thousands of viruses, they fell into a few families. Those include the H1N1 swine flu family; some of the more familiar H2N2 and H3N2; and the H5N1, or bird flu - which researchers including Kim describe as a "very scary virus."

Then computers crunched each family's DNA to find what they had in common. Inovio used that data to create what Kim calls its "secret sauce" - a formula that replicates the common elements and gives people vaccinated a broader target for their immune system.

Inovio reports it has successfully tested vaccines for each family of viruses on both animals and humans. The next phase would be to combine them for a universal version.

"That's really the holy grail for vaccine discovery," Kim said.

NIH's [Dr. Gary Jan Nabel (born 1953)] is cautiously optimistic.

"You learn over time that clinical trials are the big hurdle and because you start a trial doesn't mean it will work," he said. "But I think it's not unreasonable to hope."

And he expects someone will cross the finish line in five to 10 years.

Our bodies make roughly 20,000 different kinds of proteins, from the collagen in our skin to the hemoglobin in our blood. Some take the shape of molecular sheets. Others are sculpted into fibers, boxes, tunnels, even scissors.

A protein’s particular shape enables it to do a particular job, whether ferrying oxygen through the body or helping to digest food.

Scientists have studied proteins for nearly two centuries, and over that time they’ve worked out how cells create them from simple building blocks. They have long dreamed of assembling those elements into new proteins not found in nature.

But they’ve been stumped by one great mystery: how the building blocks in a protein take their final shape. David Baker, 55, the director of the Institute for Protein Design at the University of Washington, has been investigating that enigma for a quarter-century.

Now, it looks as if he and his colleagues have cracked it. Thanks in part to crowdsourced computers and smartphones belonging to over a million volunteers, the scientists have figured out how to choose the building blocks required to create a protein that will take on the shape they want.

In a series of papers published this year, Dr. Baker and his colleagues unveiled the results of this work. They have produced thousands of different kinds of proteins, which assume the shape the scientists had predicted. Often those proteins are profoundly different from any found in nature.

This expertise has led to a profound scientific advance: cellular proteins designed by man, not by nature. “We can now build proteins from scratch from first principles to do what we want,” said Dr. Baker.

Scientists soon will be able to construct precise molecular tools for a vast range of tasks, he predicts. Already, his team has built proteins for purposes ranging from fighting flu viruses to breaking down gluten in food to detecting trace amounts of opioid drugs.

William DeGrado, a molecular biologist at the University of California, San Francisco, said the recent studies by Dr. Baker and his colleagues represent a milestone in this line of scientific inquiry. “In the 1980s, we dreamed about having such impressive outcomes,” he said.

Every protein in nature is encoded by a gene. With that stretch of DNA as its guide, a cell assembles a corresponding protein from building blocks known as amino acids.

Selecting from twenty or so different types, the cell builds a chain of amino acids. That chain may stretch dozens, hundreds or even thousands of units long. Once the cell finishes, the chain folds on itself, typically in just a few hundredths of a second.

Proteins fold because each amino acid has an electric charge. Parts of the protein chain are attracted to one another while other parts are repelled. Some bonds between the amino acids will yield easily under these forces; rigid bonds will resist.

The combination of all these atomic forces makes each protein a staggering molecular puzzle. When Dr. Baker attended graduate school at the University of California, Berkeley, no one knew how to look at a chain of amino acids and predict the shape into which it would fold. Protein scientists referred to the enigma simply as “the folding problem.”

The folding problem left scientists in the Stone Age when it came to manipulating these important biological elements. They could only use proteins that they happened to find in nature, like early humans finding sharp rocks to cut meat from bones.

We’ve used proteins for thousands of years. Early cheese makers, for example, made milk curdle by adding a piece of calf stomach to it. The protein chymosin, produced in the stomach, turned liquid milk into a semisolid form.

Today scientists are still looking for ways to harness proteins. Some researchers are studying proteins in abalone shells in hopes of creating stronger body armor, for instance. Others are investigating spider silk for making parachute cords. Researchers also are experimenting with modest changes to natural proteins to see if tweaks let them do new things.

To Dr. Baker and many other protein scientists, however, this sort tinkering has been deeply unsatisfying. The proteins found in nature represent only a minuscule fraction of the “protein universe” — all the proteins that could possibly be made with varying combinations of amino acids.

“When people want a new protein, they look around in nature for things that already exist,” Dr. Baker said. “There’s no design involved.”

Crowdsourced Discovery

Dr. Baker has an elfin face, a cheerful demeanor, hair that can verge on chaotic, and a penchant for wearing T-shirts to scientific presentations. But his appearance belies a relentless drive.

After graduating from Berkeley and joining the University of Washington, Dr. Baker joined the effort to solve the folding problem. He and his colleagues took advantage of the fact that natural proteins are somewhat similar to one another.

New proteins do not just pop into existence; they all evolve from ancestral proteins. Whenever scientists figured out the shape of a particular protein, they were able to make informed guesses about the shapes of related ones.

Scientists also relied on the fact that many proteins are made of similar parts. One common feature is a spiral stretch of amino acids called an alpha helix. Researchers learned how to recognize the series of amino acids that fold into these spirals.

In the late 1990s, the team at the University of Washington turned to software for individual studies of complex proteins. The lab decided to create a common language for all this code, so that researchers could access the collective knowledge about proteins.

In 1998, they launched a platform called Rosetta, which scientists use to build virtual chains of amino acids and then compute the most likely form they will fold into.

A community of protein scientists, known as the Rosetta Commons, grew around the platform. For the past twenty years, they’ve been improving the software on a daily basis and using it to better understand the shape of proteins — and how those shapes enable them to work.

In 2005, Dr. Baker launched a program called Rosetta@home, which recruited volunteers to donate processing time on their home computers and, eventually, Android phones. Over the past 12 years, 1,266,542 people have joined the Rosetta@home community.

Step by step, Rosetta grew more powerful and more sophisticated, and the scientists were able to use the crowdsourced processing power to simulate folding proteins in greater detail. Their predictions grew startlingly more accurate.

The researchers went beyond proteins that already exist to proteins with unnatural sequences. To see what these unnatural proteins looked like in real life, the scientists synthesized genes for them and plugged them into yeast cells, which then manufactured the lab’s creations.

“There are subtleties going on in naturally occurring proteins that we still don’t understand,” Dr. Baker said. “But we’ve mostly solved the folding problem.”

Proteins and Pandemics

These advances gave Dr. Baker’s team the confidence to take on an even bigger challenge: They began to design proteins from scratch for particular jobs. The researchers would start with a task they wanted a protein to do, and then figure out the string of amino acids that would fold the right way to get the job done.

In one of their experiments, they teamed up with Ian Wilson, a virologist at Scripps Research Institute, to devise a protein to fight the flu.

Dr. Wilson has been searching ways to neutralize the infection, and his lab had identified one particularly promising target: a pocket on the surface of the virus. If scientists could make a protein that fit snugly in that pocket, it might prevent the virus from slipping into cells.

Dr. Baker’s team used Rosetta to design such a protein, narrowing their search to several thousand of chains of amino acids that might do the job. They simulated the folding of each one, looking for the combinations that might fit into the viral niche.

The researchers then used engineered yeast to turn the semifinalists into real proteins. They turned the proteins loose on the flu viruses. Some grabbed onto the viruses better than others, and the researchers refined their molecular creations until they ended up with one they named HB1.6928.2.3.

To see how effective HB1.6928.2.3 was at stopping flu infections, they ran experiments on mice. They sprayed the protein into the noses of mice and then injected them with a heavy doses of influenza, which normally would be fatal.

But the protein provided 100 percent protection from death. It remains to be seen if HB1.6928.2.3 can prove its worth in human trials.

“It would be nice to have a front-line drug if a new pandemic was about to happen,” Dr. Wilson said.

HB1.6928.2.3 is just one of a number of proteins that Dr. Baker and his colleagues have designed and tested. They’ve also made a molecule that blocks the toxin that causes botulism, and one that can detect tiny amounts of the opioid fentanyl. Yet another protein may help people who can’t tolerate gluten by cutting apart gluten molecules in food.

Last week, Dr. Baker’s team presented one of its most ambitious projects: a protein shell that can carry genes.

The researchers designed proteins that assemble themselves like Legos, snapping together into a hollow sphere. In the process, they can also enclose genes and can carry that cargo safely for hours in the bloodstream of mice.

These shells bear some striking resemblances to viruses, although they lack the molecular wherewithal to invade cells. “We sometimes call them not-a-viruses,” Dr. Baker said.

A number of researchers are experimenting with viruses as a means for delivering genes through the body. These genes can reverse hereditary disorders; in other experiments, they show promise as a way to reprogram immune cells to fight cancer.

But as the product of billions of years of evolution, viruses often don’t perform well as gene mules. “If we build a delivery system from the ground up, it should work better,” Dr. Baker said.

Gary Nabel, chief scientific officer at Sanofi, said that the new research may lead to the invention of molecules we can’t yet imagine. “It’s a new territory, because you’re not modeling existing proteins,” he said.

For now, Dr. Baker and his colleagues can only make short-chained proteins. That’s due in part to the cost involved in making pieces of DNA to encode proteins.

But that technology is improving so quickly that the team is now testing longer, bigger proteins that might do more complex jobs — among them fighting cancer.

In cancer immunotherapy, the immune system recognizes cancer cells by the distinctive proteins on their surface. The immune system relies on antibodies that can recognize only a single protein.

Dr. Baker wants to design proteins that trigger a response only after they lock onto several kinds of proteins on the surface of cancer cells at once. He suspects these molecules will be better able to recognize cancer cells while leaving healthy ones alone.

Essentially, he said, “we’re designing molecules that can do simple logic calculations.” Indeed, he hopes eventually to make molecular machines.

Our cells generate fuel with one such engine, a gigantic protein called ATP synthase, which acts like a kind of molecular waterwheel. As positively charged protons pour through a ring of amino acids, it spins a hundred times a second. ATP synthase harnesses that energy to build a fuel molecule called ATP.

It should be possible to build other such complex molecular machines as scientists learn more about how big proteins take shape, Dr. Baker said.

“There’s a lot of things that nature has come up with just by randomly bumbling around,” he said. “As we understand more and more of the basic principles, we ought to be able to do far better.”

Betsy Nabel, M.D., is stepping down as the president of Brigham and Women’s Hospital to enter biotech. Nabel is reportedly set to join her husband, the former chief scientific officer of Sanofi, at a stealthy new biotech startup.

Brigham appointed Nabel, a cardiologist and biomedical researcher, as its president in 2010. During her 11-year spell at the head of Brigham, Nabel tried to increase the hospital’s role in developing health technologies, including by establishing a Translational Accelerator to support researchers with ideas for new interventions.

The initiatives overseen by Nabel transformed the finances of Brigham, increasing revenues from $2.9 billion to $4.3 billion over her tenure, and exposed her to biotech. With her husband Gary Nabel leaving Sanofi to set up a biotech, the Brigham president is moving into for-profit drug development. 

Talking to The Boston Globe, Nabel said she will start working with her husband at a biotech startup focused on immune therapies for cancer and infectious diseases when she leaves Brigham on March 1. Gary Nabel stepped down as CSO of Sanofi last year but has said nothing publicly of his plans.

Betsy Nabel’s post-Brigham plans extend beyond the biotech she is setting up with her husband. If the departing Brigham president gets her way, Nabel is a name that will crop up again and again in the years to come. 

“I’m very interested in early-stage biotech development where you take a scientific idea, where you start a new company, you develop a scientific vision and strategy and business plan … you seek investors,” Nabel told the Globe. “I really want to spend time driving biotech innovation by advising companies and serving on boards. This is where I believe I can have the greatest impact.”

Betsy Nabel joined the board of Moderna in an individual capacity in 2015. That position became a point of controversy in 2020. Nabel penned an op-ed that argued the “innovation ecosystem is now under assault” from politicians who want to impose price controls, without disclosing that as a board member at Moderna she gets stock option awards and other payments from a company that would be affected by the legislation she opposed. 

Nabel resigned from Moderna’s board in July, days after Brigham took a leading role in a phase 3 clinical trial of the biotech’s COVID-19 vaccine. Moderna Chairman Noubar Afeyan, Ph.D., saidNabel’s exit was “out of an abundance of caution to avoid any potential of even apparent conflict of interest on her part or Moderna’s part.” 

The action failed to quell the criticism. Nabel came under fire for selling $8.5 million in Moderna stock in the run-up to her resignation from the board. Like other Moderna shareholders, Nabel benefited from surges in the biotech’s stock as it emerged as a leader in the COVID-19 vaccine race. This week, the Lown Institute included Nabel in the “Shkreli Awards,” which recognize “the worst actors of the US health system” for “profiteering and dysfunction in healthcare.”

Editor's note: An earlier version of this article wrongly stated the BMJ issued the “Shkreli Awards.” The Lown Institute issued the awards.