CAMBRIDGE, Mass., Jan. 15 1(AP)— A crowd of protesters abandoned their sit‐in at the offices of the top officials of Massachusetts Institute of Technology tonight, leaving the offices “a shambles,” in the words of a spokesman fort the school. 

Officials counted 55 persons walking out of the offices of Howard W. Johnson, M.I.T.'s president, and James R. Killian Jr., the corporation chairman. Not all were M.I.T. students, the officials said.

A spokesman said slogans and obscenities had been scrawled on the walls of the offices and reception rooms, and that obscenities were found in red paint on the carpeting.

Desks were overturned, doors broken and file cabinets damaged.

A spokesman said the students left of their own accord.

The invasion ended 34 hours after four young men, wearing ski masks and wielding welder pipe battering ram, smashed their way into President Johnson's office.

The demonstrators had a list of demands, all of which were rejected by M.I.T.

Dr. Paul Gray, the university's associate provost, told newsmen that the administration would “not negotiate at the point of a gun.”

Dr. Gray said that administration officials were meeting continuously on the takeover and had discussed calling in the civil authorities to remove the demonstrators. He said this seemed to be the only alterna tive in dealing with the partici pating nonstudents, whom he estimated at 50 per cent of the demonstrators.

Dr, J. D. Nyhart, dean of student affairs, told the pro testers they could face criminal charges.

“You're considered trespass ers,” Dr. Nyhart told them, “subject to prosecution under the laws of Massachusetts without further notice.”

?Students for a Democratic Society, was described by the protesters as their response to M.I.T.'s failure to meet demands by a 5 P.M. Wednesday deadline.

The demands were that the university rescind discipline meted out to students who participated in earlier demonstrations, and that it abolish the disciplinary committee.

A new demand, that M.I.T. make a gift of $150,000 to the Black Panther party was presented today.

A metal table leg was thrown through a window of Mr. John son's campus home. A note was attached to it, but its contents were not disclosed.

About 1,000 students and faculty members met this after noon at Kresge Auditorium to discuss the seizure. Newsmen were not admitted.

Biological warfare experts are concerned that countries like Iraq may be able to create forms of anthrax that can overcome the vaccine now being given to American troops in the Persian Gulf.

The concern stems from recent evidence that the Soviet Union may have mixed together several strains of anthrax, presumably to enhance the lethality of its germ weapons. Further questions have been raised by separate reports that Russian scientists have produced strains of anthrax genetically engineered to produce new toxins.

Any country with a modern microbiology laboratory could perform these manipulations, although experts differ over how effective they would be in producing a germ weapon that could thwart the American vaccine.

The vaccination program, under which all 2.4 million American military personnel are eventually to be immunized, has been criticized by Citizen Soldier, an advocacy group for veterans, which says the vaccine's efficacy is unproved. Given the risk of side effects, the group argues, the vaccine should not be administered.

Army experts and other scientists say the vaccine is effective, although much of the evidence is necessarily indirect, since battlefield anthrax cannot ethically be tested on people. They also believe that the vaccine cannot be circumvented by use of multiple anthrax strains.

Anthrax is a biological weapon of choice because the bacillus forms a sturdy, long-lasting spore and is deadly when inhaled unless antibiotics are given immediately. It is one of the agents Iraq is known to have had in its arsenal.

The American vaccine has protected people who handle goat and sheep wool from cutaneous anthrax, the usually nonlethal form of the disease that attacks the skin. But its efficacy against inhalation anthrax, the form that would threaten troops on the battlefield, is harder to assess.

Experts agree that the vaccine is not perfect. ''The protective efficacies of both the U.K. and U.S. vaccines are less than ideal,'' a British anthrax expert, Dr. Peter C. B. Turnbull, wrote in 1991. The vaccine was first licensed in 1970, and its design has not changed since. But it is the only anthrax vaccine that is available and approved by the Food and Drug Administration.

The vaccine's defenders say it has a long record of safety and effectiveness. There are no permanent side effects of any kind, and only some 2 to 4 percent of those immunized experience significant local reactions at the injection site, said Dr. Arthur M. Friedlander, chief bacteriologist at the Army Medical Research Institute of Infectious Diseases, at Fort Detrick, Md.

Studies show that the vaccine defends only 20 percent of guinea pigs against airborne anthrax spores, a point emphasized by Citizen Soldier. But, Dr. Friedlander said, it protects more than 95 percent of rhesus monkeys, which are more similar to humans. In tests, the vaccinated monkeys survive even when given doses of anthrax that are hundreds of times greater than the amount that kills 50 percent of an unprotected population.

The only time the vaccine has been tested against inhalation anthrax in humans was among mill workers in the early 1960's, when the disease was still common in the United States. Only five cases of inhalation anthrax occurred among the workers during the study period, none of them among those vaccinated. But the numbers were not large enough to prove in a statistically meaningful way that the vaccine was effective against inhaled anthrax spores, the authors of the study wrote.

Even if the vaccine is effective against ordinary anthrax, some critics of the Army's policy are concerned that an adversary could manipulate the bacillus so as to overwhelm the it. ''One would have to be a fool to believe Iraq could not make a strain resistant to the vaccine,'' said Dr. Meryl Nass, a physician who advises Citizen Soldier.

Concern that the vaccine can be sidestepped has been fanned by recent news of Russian activities. In 1979 an accident at a Soviet biological warfare center killed some 70 people in the city of Sverdlovsk, now Ekaterinburg. From autopsy tissues that came into American hands, scientists led by Dr. Paul J. Jackson of the Los Alamos National Laboratory inferred this January that at least four strains of anthrax had been present. The purpose of such a mixture, Dr. Jackson suggested, might have been to overwhelm the American vaccine.

That vaccine works by disabling a component of anthrax known as protective antigen, which helps the microbe's two toxins penetrate the cells they are attacking. Dr. Friedlander said all known strains of anthrax share the same basic form of protective antigen. For this reason, he said, the vaccine should be equally effective against any combination of strains.

It is relatively easy to make bacteria resistant to antibiotics. But, Dr. Friedlander said, it is quite difficult to alter the protective antigen without making the anthrax bacillus ineffective as a weapon. So the United States' defensive strategy against anthrax has always focused on having a good vaccine.

Russian scientists recently caused consternation by reporting at a scientific conference that they had made an anthrax strain resistant to antibiotics. But, American officials say, there was a benign explanation for the research. Russia relies on a vaccine made from a live but nonlethal strain of the anthrax bacterium. Making the vaccine strain resistant to antibiotics, which would otherwise kill it, would allow physicians to give the vaccine and antibiotics simultaneously to anyone exposed to anthrax. (The American vaccine does not contain live bacteria.)

Western experts have found it harder to find innocent explanations for a second Russian experiment, published recently in the journal Vaccine.

The experiment involved inserting toxin-making genes from a closely related and usually harmless microbe, Bacillus cereus, into the Russian vaccine strain. The apparent purpose was to create a vaccine effective against a natural anthrax strain that produced these toxins. No such strain is known to exist.

The Russian scientists, who work at the Obolensk State Research Center for Applied Microbiology, near Moscow, reported that this engineered strain of anthrax killed hamsters that had received the ordinary Russian vaccine.

Dr. Friedlander said there was no way of knowing whether the American vaccine would protect against such a genetically changed organism, which probably kills by a different mechanism.

But he said it was also far from clear that this organism could be developed into a weapon that would kill people after being inhaled. The Russian research, Dr. Friedlander said, showed only that the engineered organism killed hamsters after injection.

Capt. Jason Nietupski, a U.S. army reservist, initially thought nothing of it when the military ordered him to get a vaccine against anthrax.

Mr. Nietupski received the shot -- a standard army precaution against enemy biological attacks -- before his deployment to Korea last year. But soon after his first inoculation in February, the 29-year-old Mr. Nietupski showed up at an urgent-care facility with sores all over his mouth and throat. "The side of my tongue was all raw with little canker sores, and bloody mucus was coming out of my nose," Mr. Nietupski says.

His maladies, ultimately diagnosed as an autoimmune disorder in which his body accidentally attacked itself, grew worse as he got the next two installments of the six-shot regime. Mr. Nietupski, and several of the doctors who have examined him, believe the anthrax vaccine caused his severe reaction, and may also be to blame for the blood clots Mr. Nietupski experienced in his legs months later. The clotting problem is so serious that he can no longer jog, or even stand for very long.

Mr. Nietupski's case, and hundreds of others in which soldiers claim harm or disability from the shots, has put the U.S. military in a difficult position. It curbed the anthrax vaccination program in the wake of quality-control problems and complaints about side effects. Yet the armed forces are now in the midst of a massive mobilization in which troops are likely to confront terrorists, the kind of people widely viewed as most likely to use biological weapons.

Returning to wider inoculations risks sparking major protests, and even resistance. To date, 102 people have been court-martialed for refusing to take the vaccine, according to the Department of Defense. Hundreds of others have resigned to avoid taking the vaccine, according to critics of the military's program.

Minimum Level

Since 1998, only about 521,000 people have gotten some or all of the shots, which must be given six times over an 18-month schedule. Over the past year, vaccination has continued at a minimum level, with only high-risk personnel -- such as those going overseas -- getting the shots. There are about 2.4 million people serving in the military and its reserves.

"The manufacturer has been unable to pass a single inspection," says Capt. Dale Saran, a U.S. military lawyer who defended two of those court-martialed for refusing to take the vaccine, which was licensed by the U.S. Food and Drug Administration in 1970 and is now made by BioPort Corp., of Lansing, Mich. "No vaccine today would be made with these procedures."

BioPort concedes that the FDA has found deficiencies every time it inspected the plant since it bought it in 1998. But it says it has either corrected them or is in the process of doing so. The U.S. Army acknowledges that more than 30% of those getting the vaccine have experienced minor side effects, but they say serious problems are highly unusual.

Easy to Obtain

Anthrax, normally a scourge of livestock, is rare in humans. But it is viewed by the government as one of the top seven most likely biological weapons, along with smallpox and pneumonic plague. The reason is that it is fairly easy to obtain, from the soil or from infected animals, and very deadly. Without prompt treatment, the disease kills an estimated 90% of those exposed.

Before Sept. 11, the future of the anthrax vaccination program looked uncertain. The effort, begun by the Clinton administration in 1998 after intelligence found Iraq and other enemies might be developing anthrax-based weapons, ran into problems nearly as soon as it started. That same year, after the FDA found myriad problems with the plant's sterility and quality, BioPort shut it down for renovations. And, even though there were enough doses already made to continue vaccination, skeptical military employees began digging in their heels. BioPort says it has made some vaccine since 1998, but that it won't be released for use until the FDA clears the plant.

President Bush, during his election campaign, told U.S. Medicine, a trade publication focusing on federal health policies, that the anthrax vaccination effort "has raised numerous health concerns and caused fear among the individuals whose lives it touches." He added, "Under my administration, soldiers and their families will be taken into consideration." A Defense Department memo dated Aug. 10 outlined plans to "review and assess" the performance of BioPort, and to develop long-range plans to replace it with a "dedicated vaccine facility to serve the national interest."

But today, flaws and all, closely held BioPort has become a key national-security asset. Three employees of tabloid publisher American Media Inc. have been exposed to anthrax in Florida, in what investigators suspect was a criminal act. The Department of Health and Human Services, after a long silence on the matter, has said in recent days that the FDA is working closely with BioPort and hopes to be able to reopen the facility within six weeks -- rather than in the three or four months expected earlier.

The government's statements "are a clear indication that they plan to cut corners to make this happen," says Col. John Richardson, a Chapel Hill, N.C., pilot who retired from the U.S. Air Force last year in part due to concerns about the military's mandatory vaccine policy.

Vaccination Is Critical

Vaccination against anthrax is critical because it is difficult to detect an attack early enough to save the victims. One of the three America Media employees who were exposed to the disease died despite doses of antibiotics. Due to potential side effects, and the inconvenience of repeated shots, it's unlikely that a preventive anthrax vaccine would be given to the public. However, many experts believe that such a vaccine would be useful after an exposure, because animal studies have shown anthrax can survive in a dormant form for at least a month even with heavy antibiotic therapy.

Since 1970, the sole U.S. supplier of anthrax vaccine has been a laboratory in Lansing formerly owned by the state of Michigan. The state decided in the mid-1990s to put the facility up for sale, but there was scant interest from major pharmaceutical firms. In early 1997, the FDA issued a notice that it planned to revoke the lab's license after a failed inspection.

Enter Fuad El-Hibri. Mr. El-Hibri had previously been a director of a British maker of bio-defense vaccines for anthrax and botulinum. Sensing an opportunity, Mr. El-Hibri, a German national of Lebanese extraction, formed BioPort to bid for the lab. He also brought in on the deal a powerful ally, retired Adm. William J. Crowe Jr., a former chairman of the joint chiefs of staff who also served as U.S. ambassador to Britain under President Clinton. Mr. El-Hibri is now a U.S. citizen.

Mr. El-Hibri later testified before a U.S. House committee that other stakes in the company were owned by his wife Nancy and by a Netherlands Antilles company controlled by his father, Ibrahim El-Hibri. BioPort won the auction for the Michigan lab with a bid of about $24.8 million, and closed the deal in September 1998. Less than two weeks later, Bioport was awarded a $45 million, sole-source contract to supply anthrax vaccine to the Pentagon.

Adm. Crowe's involvement later raised eyebrows in Congress. The admiral clearly had high-level contacts in the Pentagon, and had been one of the few prominent former military leaders backing Mr. Clinton's election bid in 1992. In addition, congressional staffers familiar with the situation say Adm. Crowe paid only a token amount for his 22.5% original stake in a holding company that controls BioPort by owning just over half of its shares.

Adm. Crowe "was used as the man in the window" by BioPort, says Lawrence Halloran, staff director of the subcommittee on national security of the House Committee on Government Reform, which held numerous hearings on the anthrax vaccine. "He paid virtually nothing for his stake, and they got the use of his good name."

In an interview, Adm. Crowe said he had gotten to know Fuad El-Hibri after a long association with his father, and had agreed to join the company's board "because it seemed to me like a pretty good idea" to be associated with something that might help the U.S. defend against "an offensive weapon."

Adm. Crowe said he was unprepared for the "storm" of controversy his role in the company has generated, but stated "I haven't attempted to influence" the BioPort contract "in any way." The admiral also said his position as a director of the company is unpaid, adding that BioPort's financial woes have meant that "until now, not a single cent" has come from his stake in the company.

Jay Coupe, a longtime aide to Adm. Crowe who acts as his spokesman, said the admiral "didn't pay anything" for his stake in BioPort, which he said was the equivalent of about 12% or 13% of the company. "As is the case with a lot of former government officials, one of the incentives to bring him on board was a piece of the action. Unfortunately, the action has been nonexistent."

Mr. Coupe said the admiral strongly believes the anthrax vaccine program is right for the troops he used to command, and has taken the six-shot course himself.

Mr. Halloran says the Defense Department, when it focused on bioterror after the Gulf War, could have taken the time to develop a new vaccine that only had to be given once or at most three times, with predictable characteristics. Instead, he says, "they took the easy way out" and selected the vaccine which was originally developed in the 1950s and reformulated in the 1960s. "Now we're stuck with this thing."

In 1998, shortly after taking over the plant, BioPort decided its problems were so grave that it needed to be shut for a major overhaul. In August 1999, the government gave the company an additional $24.1 million in "extraordinary contractual relief," according to a Defense Department report, and restructured the original deal so that the company would be paid between two and five times more per dose, for a smaller number of doses.

Found Wanting

But even after the financial boost and extensive renovations, Bioport's plant was found wanting in a November 1999 inspection, and again in October of last year. In a report dated Oct. 26, the FDA lists three pages of reasons why a section of the plant where vials are filled with the anthrax vaccine and other products does "not assure sterility." Specifically, inspectors found rust on equipment, including an oven in the plant, and saw smoke seeping into an area where it should not be. Also, the FDA report said, "employees routinely exit and enter" through a curtain into a room where product is located and "do not always sanitize their hands" after touching the curtain. The curtain, the report says, was "discolored," possibly from rust.

Andrew J. Bacevich, director of the Center for International Relations at Boston University, who has studied the anthrax-vaccine program, says it has been "massively mismanaged" by BioPort and by the Pentagon. BioPort has a "horrible track record in terms of its performance" and yet the Department of Defense "seems to think the answer is to give them more time and more money."

Tom Waytis, vice president of medical affairs at BioPort, acknowledges that the plant has had some sterility problems -- for example, at one point, tests of empty vials found bacteria. However, all product made in the plant at that time have been put aside in a location he won't disclose. "There never has been a contaminated product released," he said. The company is planning to submit its final application to the FDA for plant certification by Monday.

Lt. Col. John Grabenstein, an army epidemiologist who tracks reactions to the vaccine, says negative side effects are "minimal" given that some 2.1 million doses have been given to 521,000 people since 1998. Some 1,628 of those people have reported problems after getting the vaccine, mainly redness or swelling at the site of the injection. Ten had such massive swelling in their arms after the vaccine that they needed to be hospitalized, a reaction which Dr. Grabenstein acknowledges was probably caused by the vaccine. An additional 15 were successfully treated for anaphylaxis, a potentially fatal allergic reaction, which can cause lungs to spasm and the throat to swell up.

But critics of the vaccine, mostly current or former military personnel, say the official side-effect numbers are artificially low because the military discourages reporting them. Mr. Nietupski says that, although he was examined by more than a dozen military doctors since his symptoms began in February of last year, none of them initially reported them to the FDA. Only in March, a year later, after Mr. Nietuspski complained to members of Congress, was his case reported.

The Department of Defense says it encourages reports of vaccine side effects by doctors, and that patients may even submit the reports themselves if they like.

Six people have died within a short time after getting the vaccine, according to reports made to the FDA. Three died of some sort of cardiovascular problem, one committed suicide, one had cancer and another, Sgt. Sandra L. Larson, died in June of last year of a rare blood disorder. Dr. Grabenstein says a panel of civilian experts have looked at the deaths and found no evidence they were caused by the vaccine. "People are saying 'I'm sick and I've been vaccinated.' I'm sorry that you're sick, but A following B doesn't mean A caused B," he says. "It's far more intricate than that."

Dr. Grabenstein says that the disorder experienced by Mr. Nietupski, called Stevens-Johnson Syndrome, could possibly have been caused by the anthrax vaccine, given that it has been linked to some other types of vaccines. However, he says, the blood clots are very unlikely to have been caused by the vaccine. He says the civilian expert panel, called the Anthrax Vaccine Expert Committee, hasn't ruled on Mr. Nietupski's case yet.

Meryl Nass, an internist in Freeport, Maine, who has treated several military personnel who have developed chronic fatigue and other ailments, says she believes Sgt. Larson's death and at least one of the others she is familiar with could have been caused by the vaccine, through a sort of "autoimmune reaction," in which the body's defenses go on overdrive after getting the vaccine and accidentally destroy its own tissues.

Sgt. Larson, 32 years old, started to feel sick after getting her final anthrax shot in March of last year. She noticed rashes on her arms and legs and felt constantly tired. In April, after she began to hemorrhage, she was admitted to the intensive care unit at Kansas City Medical Center, and diagnosed with aplastic anemia, or a severe lack of blood cells. In the hospital, convinced her malady was caused by the anthrax vaccine, Sgt. Larson began to do some of her own research. Two months later, on June 14, she died.

Autoimmune Reaction

Dr. Nass, who reviewed Sgt. Larson's case after her death, believes her malady could have been caused by the vaccine, as a result of an autoimmune reaction in which the body attacks its own blood cells. In another case, BioPort employee Richard Dunn, who received the vaccine to protect him against possible exposure to anthrax on the job, was found to have died from a heart attack after "polyarteritis nodosa," an autoimmune disease in which the body mistakenly attacks its own arteries.

Medically, there's no way to tell whether any individual problem was caused by the vaccine. The only reliable method is to look at large groups to see whether particular maladies are more common in those who have been vaccinated than in the general population. Dr. Grabenstein says 18 studies have found no higher incidences of serious maladies, such as blood clots or autoimmune disorders, among those getting vaccines.

But few of those studies, which include many by military scientists and some work dating back to the 1960s, have been "peer reviewed," or examined by experts prior to publication. In a 1999 report, the Institute of Medicine found "insufficient evidence" to determine whether the anthrax vaccine is safe or not. The IOM is now preparing another report on the matter, and Dr. Grabenstein says the military is "pleased" with where it appears to be headed. The IOM couldn't immediately be reached for comment.

Sgt. Larson's sister, Nancy Rugo, of Spokane, Wash., is now continuing her search for answers. Before Sgt. Larson died, she told her sister "be sure you finish this search for me, because I know it's the vaccine," Ms. Rugo says. Ms. Rugo, following through on her sisters' wishes, is comparing notes with others' whose family members have died or suffered serious disability after getting the shots. "As far as I'm concerned," says Ms. Rugo, "this is an unsolved mystery."

As anthrax exposures continue and the specter of smallpox has loomed on the horizon, many officials have begun discussing widespread vaccination against the two diseases in an effort to reduce public concern about terrorist threats.

But the vaccines now in use present a number of problems--ranging from lack of manufacturing capacity to side effects--that render large-scale vaccination programs problematic.

Medical researchers have been working on efforts to produce safer vaccines. But until now, drug companies have put relatively little money into what has been considered a low-margin, low-priority part of the business.

For both anthrax and smallpox, the side effects of the vaccines are serious enough that widespread vaccination could cause more damage than the diseases themselves unless the vaccines are used only after a major outbreak has begun.

Anthrax vaccination of soldiers has produced reports of severe side effects, such as bleeding and thyroid malfunction, and has been linked to six deaths.

Just what degree of risk there is from the vaccine, however, is unclear. Many medical authorities say it is safe, but some doctors have suggested it could be one of the causes of the mysterious Gulf War syndrome, which some troops sent to the Persian Gulf in the early 1990s have said they suffer from

Fear of the vaccine is perhaps greater than fear of anthrax. As many as 400 members of the U.S. military have been court-martialed or have resigned rather than submit to the vaccination because of the perceived risks. Some physicians share their misgivings.

“You won’t see me getting in line for the vaccine,” says [Meryl Jae Nass, MD (born 1951)], a longtime critic.

The vaccine is produced by only one manufacturer, BioPort Corp. of Lansing, Mich., and the technology is nearly 40 years old. Although the company is currently producing the vaccine, the Food and Drug Administration will not allow it to be shipped because of various deficiencies in quality control and manufacturing at the plant.

The vaccine is unusual in that it is not targeted at the bacterium itself, as are most vaccines, but at the toxin produced by the bacteria as they grow. That toxin produces the cellular damage that can lead to death from an anthrax infection.

The toxin has three major components: protective antigen, lethal factor and edema factor. When the toxin is released in the body, individual molecules of the protective antigen clump together on the surface of target cells to form a doughnut-shaped pore. This pore is then used by the other two components to enter the cell, where they are lethal.

The vaccine is designed to stimulate antibodies to the protective antigen, preventing it from attaching to cells. In theory, if the action of the toxin is blocked, then the immune system can eradicate the bacteria or they can be killed with antibiotics.

“We buy the individual some time to fight off the infection,” said microbiologist [Dr. Darrell Ray Galloway (born 1946)] of Ohio State University.

BioPort grows a strain of Bacillus anthracis that secretes only protective antigen. The bacterial culture is filtered--in a process much like making coffee in a filter pot--to collect the antigen along with any other materials that are secreted by the bacterium. The material that drips through the filter becomes the vaccine. It contains no bacteria, either dead or alive.

But the antigen does not stimulate a strong immune response. To get good immunity, six doses of the vaccine must be given at two-week intervals.

Critics fear that the other bacterial components collected along with the antigen may cause side effects, so research has focused on eliminating them.

“The interest is in more highly defined vaccines so one knows precisely what one is being immunized with,” Galloway said.

The Army has been working with the National Institutes of Health to use genetic engineering techniques to produce a pure antigen. Although both the military and the NIH have consistently refused to talk about their work, other experts say that human tests will begin early next year. That vaccine will also require multiple doses.

In his research, [Dr. Darrell Ray Galloway (born 1946)] also is targeting the toxin. But instead of using the antigen protein itself, he is injecting mice with the gene that causes the body to produce the protein. Researchers have been producing such DNA vaccines against a variety of diseases, and they are generally thought to produce a more powerful immune response and fewer side effects than standard protein vaccines.

He also uses the gene for the lethal factor in his vaccine. “We get a greater response with both than with one alone,” he said. Preliminary results in mice reported earlier this year indicate that the DNA vaccine can blunt anthrax infections, but Galloway must conduct many more tests, including vaccination of primates, before use of the vaccine in humans can be considered.

The most optimistic estimate would be 18 to 24 months before clinical trials could begin, he said.

The smallpox vaccine produces a different set of problems. Like the anthrax vaccine, it employs old technology--dating back to experiments by Edward Jenner, the pioneer of vaccines, in 1796.

Smallpox is produced by a virus called variola, but researchers do not use it to produce the vaccine. Instead, they use a related virus called vaccinia, which produces a disease called cowpox.

The normally mild infection produced in humans by the live vaccinia provides very good protection against smallpox--so good that the disease has been eradicated from nature. Today, variola is known to exist only in one laboratory each in the United States and Russia, although U.S. officials suspect that Iraq and perhaps other nations may also possess some virus stocks.

“The risk of its being used as a weapon is not very high, but it’s there,” said [Dr. Donald Ainslie Henderson (born 1928)] of Johns Hopkins University, who ran the global smallpox eradication campaign. “And if you got an outbreak, it would be a terrible global catastrophe.”

Existing stocks of the smallpox vaccine were grown in calf cells, collected and freeze-dried more than 30 years ago.

The vaccines are believed to still be effective, but they are contaminated with proteins and other materials from the cow cells that may produce adverse reactions in some individuals.

New Rules From the FDA

The FDA no longer allows vaccines to be grown in animal cells. The new contracts for vaccine production recently signed with several companies require that vaccinia be grown in human cells. That process is straightforward and should not introduce difficulties, and manufacturers assume that the new vaccine will be as effective as the old one.

“There are no technical hurdles here,” said Lance Gordon, chief executive of vaccine manufacturer [VaxGen, Incorporated]. “Everything that has to be done to make a state-of-the-art smallpox vaccine is technology already in use.”

But critics caution that a smallpox vaccine grown in human cells has never been tested and that assumptions don’t always hold up.

Vaccinia, moreover, can itself produce problems ranging from open sores all over the body to death.

The death rate is estimated to be as high as 2 in a million cases, meaning that if the entire U.S. population were vaccinated, about 600 people would die of the vaccine.

Inadvertent contamination of the eye--caused perhaps by touching the vaccination site and then the eye--can produce severe problems, including blindness.

Vaccinia itself is infectious. That’s a valuable trait in a vaccination program because it provides protection to people who weren’t directly vaccinated.

But in a modern society with large numbers of people whose immune systems have been damaged, by HIV infections or as a result of drugs taken for organ transplants, that contagion could be a major problem that likely would lead to additional deaths.

All told, vaccinating all Americans against smallpox could cause 3,000 severe adverse reactions and a much larger number of lesser problems, according to [Dr. Thomas Patrick Monath (born 1940)], an executive at British vaccine manufacturer Acambis.

If a terrorist group actually launched a smallpox attack, however, “we don’t have any choice as a society” other than to use the vaccinia vaccine, said [Dr. Darrell Ray Galloway (born 1946)].

The U.S. population now is almost entirely unvaccinated--the effect of the vaccine largely wears off after about 20 years, so most people who received the vaccine as children are no longer immune. An unprotected outbreak of smallpox potentially could kill millions of people, experts say.

A small number of researchers have been exploring the possibility of using a different type of vaccine, a killed-virus vaccine, which would eliminate the danger to immunosuppressed individuals.

But development of such a vaccine, like that for anthrax, has been hindered by lack of a market, and any product is still at least a couple of years from human tests.

For that reason, officials have pushed for a major expansion of the current smallpox vaccine supply. Right now, the country has about 15 million doses, not nearly enough to contain a major outbreak.

The World Health Organization once had 200 million doses in storage in Switzerland, but the international body ran out of money to keep them, and they were destroyed after President Reagan reduced U.S. payments to the United Nations. ‘

The only laboratory in the country that makes anthrax vaccine will not be ready for a crucial federal inspection until mid-December, later than federal officials had hoped.

The lab, owned by BioPort, a private 220-employee company here, was partly dismantled for a thorough cleaning just as the anthrax attacks began in early October. Company officials say they finished cleaning on Thursday and will need several more weeks to work up to production.

The delay is the latest in a series of problems that have prevented the military from using the anthrax vaccine produced here since December 1997.

American officials are anxious enough about vaccine supplies that they have asked foreign governments for samples of their vaccines to test for possible use in the United States. A bipartisan panel on terrorism, created by Congress in 1999, recommended on Nov. 1 that a government-owned vaccine laboratory be created to produce vaccines for anthrax, smallpox and other bioterrorism threats.

''We can't expect a private contractor to gear up and fill these contracts,'' said Gov. James S. Gilmore of Virginia, a Republican who is the panel's chairman.

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But officials at BioPort say that they are close to resolving their production problems at last and making millions of doses available to the military.

Robert G. Kramer Sr., BioPort's president, said that the comprehensive cleaning of the laboratory was carefully planned so that equipment could be reassembled at any time and put back into production within 10 days. But the military never asked the company to do so, he said.

''We are taking all the prudent and precautionary steps to be ready for a very rigorous inspection by the F.D.A. while being sure that we can be back in production quickly if need be,'' Mr. Kramer said. ''It's a balancing act.'' He added that the country should have a second anthrax vaccine factory, possibly run by another company, as a precaution.

The company and the Food and Drug Administration have argued for years over quality-control problems at the Lansing laboratory. The F.D.A. has in particular criticized the sterility of the lab's process for decanting the vaccine into 10-dose vials. The company has given up trying to use its own equipment for this task, and now plans to ship the vaccine in bulk to another company, Hollister-Stier Laboratories, in Spokane, Wash., which will decant it into the vials and ship it back to Lansing.

Decanting vaccine into vials was a problem for the Lansing laboratory even before its sale to BioPort, said George Burgoyne, a BioPort critic who was the laboratory's chief of vaccine production until the state of Michigan sold it to BioPort in September 1998.

Mr. Burgoyne said the laboratory had two people sterilize vials and carry them into the room that contained the filling machine. ''No matter how you dress people, organisms come off them all the time,'' Mr. Burgoyne said.

Many drug companies, including Hollister-Stier, automated this task entirely in the 1980's and early 1990's, and the F.D.A. responded by setting more stringent standards for sterility in the vial-filling process. The state of Michigan began renovating the lab in February 1998, and BioPort completed the task in April of the following year. But the renovation did not include automating the filling process, and the laboratory failed an F.D.A. inspection in October 2000.

The inspection report describes numerous problems, especially in the filling area. Inspectors noted that insufficiently clean air was entering the area, and that employees were touching nonsterile surfaces on their way in.

BioPort has also had problems with its labeling. At the F.D.A.'s urging, the company replaced the labels on an unspecified number of anthrax vials in September 2000, after it printed inaccurate expiration dates on them. Hollister-Stier is talking with BioPort to take over the labeling, too.

The lab will work up to full production over the next several weeks in preparation for another inspection, Mr. Kramer said. If it passes the inspection this time, BioPort will ask the F.D.A. to approve the use of 600,000 vaccines already decanted by Hollister-Stier in late summer, he said. Earlier vaccines, decanted here, would be administered only under the F.D.A.'s program for new drugs, which requires close medical supervision.

BioPort and the F.D.A. have been leery of moving too quickly to resume anthrax vaccine production because the vaccine itself has long been controversial. Several hundred military personnel have refused to take it after reports that it might be linked to a wide range of illnesses, including ''Gulf War sickness,'' a combination of symptoms sometimes seen in veterans of that conflict.

Dr. Meryl Nass, a physician who advises soldiers who oppose the vaccines, said that fixing manufacturing problems was a good idea, but that the way the vaccine is produced -- by filtering toxins from anthrax bacteria -- inherently produces excessive variations in the vaccine's potency and purity.

The Defense Department, the F.D.A. and BioPort all say the vaccine, which was developed in the early 1960's, is safe. The Army is working with the drug industry to develop a new vaccine, but still has years of work ahead, a person involved in the work said.

It was the fall of 1990, a month after Saddam Hussein's army invaded Kuwait. Amid fears that Iraq would wage biological war using anthrax, a team of government scientists was commissioned to answer an urgent question: Could a prolonged course of antibiotics, anthrax vaccine, or a combination of the two keep people exposed to anthrax from getting sick?

The experiment, involving 68 rhesus monkeys and nearly as many researchers, suggested that monkeys who received both antibiotics and vaccine would fare better than those who received either vaccine or antibiotics alone. But the research, led by Arthur M. Friedlander, a senior scientist at the government's bioterrorism defense laboratory in Fort Detrick, Md., was far from definitive.

Definitive or not, Dr. Friedlander's wartime work provides the scientific underpinning for the government's announcement today that it is creating the first stockpile of anthrax vaccine for civilian use. Government officials were vague today about how the vaccine stockpile, along with an existing stockpile of antibiotics, would be used, except to say it would be offered in an emergency.

''Stockpiling the vaccine is the most prudent course for protecting our citizens' health and well-being,'' said Claude Allen, deputy secretary of health and human services.

Despite the paucity of evidence, most experts agree.

''There's no way in the world you could do a clinical trial of this in humans,'' said Dr. Philip Brachman, an anthrax expert at Emory University. ''We use the best scientific judgments we have.''

The anthrax vaccine has long been plagued by questions about its safety, with some soldiers who had been inoculated complaining of a range of illnesses. In March, an independent panel of experts at the Institute of Medicine issued a report saying the vaccine was safe and effective, even against genetically engineered strains of anthrax. Still, skeptics remained.

''It never hurts to have a stockpile,'' said Dr. Meryl Nass, an internist in Freeport, Me., who has been highly critical of the vaccine.

But Dr. Nass said she would offer it only as a last resort.

The vaccine has, in fact, already been offered to civilians. After the anthrax attacks last fall, the Centers for Disease Control and Prevention made it available to thousands of postal employees and Capitol Hill workers who had been exposed. But only 192 people took the government up on its offer.

David Ashford, an anthrax expert at the disease control centers, said he would like to see additional animal research to help public health officials better understand how to use the vaccine for ''post-exposure prophylaxis.''

Dr. Friedlander agreed.

In the monkey study, he said, researchers exposed the animals to anthrax, and gave them treatment of antibiotics, vaccine or a combination of the two. A handful of the treated animals died. After three months, the survivors were again exposed to anthrax. This time, there were deaths in each group, Dr. Friedlander said, with one exception: the animals given both antibiotics and vaccine.

The experiment, Dr. Friedlander said, began less than a month after Iraq invaded Kuwait, and lasted five months start to finish.

''I must tell you,'' he said. ''this was a wartime footing. There was an urgency like never before.''

Wednesday’s news conference certainly filled a mysterious vacuum surrounding the case against [Dr. Bruce Edward Ivins (born 1946)], who was called the sole author of the anthrax attacks that killed 5 people, with pages and pages of circumstantial evidence but no smoking guns. As Scott Shane and Eric Lichtblau reported in The New York Times today, investigators received votes of confidence as well as heaps of skepticism in return. 

That mix of reactions was reflected on the Web, where close observers of the case blogged about various elements of the evidence the Justice Department said “could prove his guilt to a jury beyond a reasonable doubt.” 

“While what I’ve seen of their case so far makes a pretty compelling argument that Ivins was involved in creating the anthrax,” Marcy Wheeler wrote on her left-leaning blog, “they’ve got nothing that explains how it walked out of Ft. Detrick, got into envelopes, and got sent to a bunch of media figures and senators.”

Meryl Nass, a vaccine expert who strongly doubted the case as outlined so far, accepted that Dr. Ivins had a strong link to the anthrax used in the letters. But she noted, citing an article in The New York Times, that at least 100 other people had similar access to the spores and that the Justice Department’s characterization of Mr. Ivins as the “sole custodian” was flawed. 

“The strain was grown in 1997, and many people had access to it over that four year period,” [ Ms. Nass wrote.  To see what she wrote, refer to  https://anthraxvaccine.blogspot.com/2008/08/beyond-reasonable-doubt.html ] “Having received a sample, or obtained it surreptitiously, they would be ‘custodians’ of it too.” 

Bruce F. Kemp, a lawyer for Dr. Ivins, made a similar point as he criticized the case, saying of the lab workers at Ft. Detrick that “they kept no records of who took a sample.”

Just as the mystery congealed into major doubts about the investigation before Wednesday, some of the most persuasive evidence cited by several bloggers rested on mysteries that emerged from Dr. Ivins.

Asked to explain his solitary late-night work at the lab in the days before the mailings, Dr. Ivins offered a vague explanation about seeking to avoid domestic problems, rather than any pressure to finish an important project, according to search-warrant application written by a postal inspector. The document also accused Dr. Ivins of misleading investigators with “false samples” of anthrax — a charge dismissed by Mr. Kemp, who said that a simple miscommunication accounted for the sample episode.

Both points, though, resonated with several bloggers. Here’s one opinion from The Reality-Based Community:

• At a minimum, Ivins’ deception indicates that he must have known that the anthrax came from his lab, either because he was involved in the attack or had an extremely good idea who was. The late-night activity in the lab (for which he had no good explanation) and the personal details cited by the F.B.I. suggest that he was involved, although it is remotely possible that circumstantial details were used by someone with detailed knowledge of his personal life to frame him. 

The blog written by The Washington Post’s investigative desk elaborated on how the off-hours lab work would have given Dr. Ivins the opportunity to prepare the attacks:

• After the story broke, some of the scientists who worked at USAMRIID with Ivins suggested that he couldn’t have carried out the attacks, because the lab did not work with dry spores and someone would have noticed what Ivins was doing. The affidavit provides a convincing rejoinder: a chart showing that Ivins was spending an usually long amount of time at nights and on weekends alone in the B3 hot suite with RMR-1029.

Dr. Nass counters, though, that it would not have been unusual for scientists in their field to burn the midnight oil after 9/11. “If Ivins was trying to work harder under the cloud of an impending attack, it makes sense to me, because I was working harder,” she wrote. If he was doing something else, Dr. Ivins apparently did not tell investigators. 

The more speculative pieces of circumstantial evidence unveiled on Wednesday, many of them pertaining to Dr. Ivins’ alleged motive, drew doubts from, among others, Glenn Greenwald, who has been a leading voice in criticizing the Justice Department’s handling of the case.

Mr. Greenwald dismissed the similarities that have been identified between the anthrax notes and e-mail messages Dr. Ivins sent around the same time. While phrases attributed to terrorists urging “death to all Jews and all Americans” were hardly unheard at the time, Mr. Greenwald’s argument that they “had long been prominent in the news” led him to cite The Journal of Counterterrorism and Security International, a relatively obscure publication.

As The New York Times reported today, the case’s major scientific findings have yet to be released, a key factor in convincing specialists that the bacteria could have been created by Dr. Ivins. 

While those holes may be filled soon by the Justice Department, another mystery seemed likely to endure. As Ace of Spades HQ, a right-leaning blogger, put it, “There is that question of bizarre timing, after all: Ivins just so happened to be finishing up his plot to send anthrax and pin it on Al Qaeda just as al Qaeda attacked America.”

In the post, the writer seemed to speak for a lot of people when he described his personal opinion about the case. “I myself was skeptical of Ivins’ guilt,” he said. “I am less so now, but I’m not entirely convinced.”