the great vaccine debate

(the polio vaccine story appears on a separate blog.  these articles initially appeared in two books I wrote.)

In 1998 Andrew Wakefield, a British doctor told of a study he did that  connected the rising incidence of autism to the Measles, Mumps, and Rubella shots of childhood.  He created a stir and found a receptive ear among growing numbers of parents.  Some had a 2, 3, or 4 year old children who didn’t speak or communicate normally; others had youngsters who were socially withdrawn or inappropriate.  They had all been advised their little one was on the “autistic spectrum”, and when they asked their doctor why this happened, many were told: “I wish I knew.”  Wakefield blamed the behavior on brain changes caused by the vaccine’s mercury preservative, the Thiomersal; his followers put pressure on their legislators.  Laws were passed and vaccine makers removed the “offending” material from the brew; but it didn’t help. 

It must be the aluminum, a mother in the audience called out.  She was one of 50 or so parents who attended the Dr. Oz T.V. inquiry.  Others in the gallery repeated her words and sounded a bit like worshipers crying “Amen.” (Dr. Oz TV show Feb 17, 2011 available on YouTube)

When Dr. Oz left medical school in 1975 Autism was a minor problem.  He showed a slide that demonstrated a 50 fold increase in the number of diagnosed cases in 35 years; one in 110 kids in this country is currently thought to have the problem.  The phenomenon (an expert explained) is in part caused by physicians who are making the diagnosis in kids with relatively minor disorders.  We’re lowering our threshold. 

Parents checked for a lack of gesturing, symbolic play, or babbling.  When a child didn’t make eye contact or respond to his or her name within the first year of life, fathers and mothers wanted to do something.  Some children, they claimed, seem to respond dramatically to a gluten and casein free diet.  .

In the years following the Wakefield report, 23 studies were performed to try to confirm or deny the correlation between childhood vaccinations and the condition.  None found a connection.  The science that refutes Wakefield, a pediatrician said, is good.  An MD colleague (on the Oz show) pointed out that parents remain skeptical because 18 of the studies were sponsored by pharmaceutical industry.  (Amen from the audience.) 

A thoughtful San Diego pediatrician wrote a book on the subject.  He worried that in the absence of immunizations we’re creating a vulnerable population.  He advocated giving one immunization at a time and spreading the doses out.  His approach created a risk which he experienced first hand when a kid incubating measles came to his office and transmitted the disease to other children in the waiting room.

There have always been people who feared vaccination, but Dr. Wakefield’s study fueled a movement.  Many young mothers in this country worry, hesitate, spread out the dose, and sometimes avoid having their child immunized. 

Dr. Wakefield’s paper and his methods were scrutinized by a British medical board.  They discredited the study and they criticized the doctor on a number of grounds. (See Wiki for details) They even took away his medical license.

He came to the U.S., kept advocating, and became the guru of many mothers.

The most prominent current vaccine critic is Jennie McCarthy, T.V. personality and former Playboy Playmate.  Her kid has autism, and (as she explained in her book) she’s convinced the vaccine caused it. 

Now that the usual illnesses of childhood aren’t staring us in the face we don’t remember how harmful they were, and most young parents can’t visualize the alternative when they make decisions about immunizing their children. 

During the 1800s, Pasteur, Jenner, and others used live viruses to produce vaccines. Their creations protected people and animals from smallpox, rabies, animal anthrax, chicken cholera, and probably a few other diseases.

During the First World War, 8 of every 1,000 injured British soldiers died or were sickened by a poison that was made by Clostridium tetani. Their condition was called tetanus, or lockjaw. The germ that made the toxin often exists in dirt. It thrives in the absence of oxygen, and gets into wounds. Eight days after a soldier was injured, the trapped bacteria had usually generated enough toxin to cause jaws to tighten, muscles to become rigid, and breathing and swallowing to become difficult.

In the late 1800s, a Scottish toxicologist created a serum that protected animals from the venom of a cobra.  Later a Japanese physician developed an antiserum that prevented “lockjaw.” The Japanese investigator, Kitsato Shibasaburo, was born in a mountainous village on the southern Japanese island of Kyushu. His government sent him to Berlin and he worked in Koch’s lab. While there, he became the first researcher to grow a pure culture of the tetanus bacillus. In 1890, he and another investigator “injected sub-lethal doses of tetanus toxin into rabbits” and produced an antitoxin. It allowed doctors to block the effect of the venom, but it didn’t prevent the condition.

In 1924, a French veterinarian named Gaston Ramon inactivated the deadly tetanus poison with formaldehyde and added an “adjuvant,” a chemical that boosts the immune response. When his creation was injected into a person, the recipient developed antibodies that blocked the tetanus toxin. Ramon also helped develop the vaccine that opposed the diphtheria toxin.  It prevented the thick throat and nose membrane that, in severe cases, obstructed airways and made breathing difficult.  Each of Gaston’s creations saved countless lives and he was nominated for the Nobel Prize 155 times, but he never won.

 

By the time the U.S. entered the Second World War, the U.S. Army was routinely using the vaccine for tetanus. Though there were over 2.5 million wounded soldiers during the conflict, only 12 developed lockjaw. Four of those individuals probably didn’t get all three shots.

In the early 20th century, researchers learned how to use viruses that were killed with formaldehyde to create immunity to various diseases. More than 40 of these types of vaccines were developed by Maurice Hilleman. The son of a farmer, Maurice was born on a hot summer day on a Montana farm near the banks of the Yellowstone and Tongue Rivers. His mother had severe complication of pregnancy called eclampsia.  Before she died, she gave her two-day-old newborn to the childless couple down the road. Maurice claims he was put to work as soon as he was able to tell a weed from a seed. “Everyone in Montana had to earn their keep.” On the farm, they sold what they grew. He picked berries and watered the animals. As a teenager, he worked at J.C. Penney in the nearby town and “helped cowpokes pick out chenille bathrobes for their girlfriends.” He decided he didn’t want to go to the local college because he “didn’t want to be strapped down by the church dogma.” He won a scholarship to Montana State University and graduated first in his class. That got him into the PhD program in microbiology at the University of Chicago. “Despite receiving a scholarship, money was always in short supply. Hilleman lived in a squalid apartment and survived on a single meal each day. At 6 feet 1 inch tall, he weighed less than 140 pounds.”

As he explained, the Chicago University professors didn’t want to be bothered unless “you discover something.” While in school, he identified an organism that was sexually transmitted.  It infected 3 million Americans a year and scarred many fallopian tubes.  It was a bacterium called chlamydia.  It only grew inside the cells of the host and it was easily destroyed by antibiotics. Hilleman’s professors tried to make him stay in academia, but he “came from a farm and wanted to do something—to make something.”

In 1944, as a new employee of Squibb, Hilleman developed a vaccine for Japanese encephalitis virus. The virus infects pigs in parts of Southeast Asia and is transmitted by mosquitoes. In humans, the infection is usually mild but it sometimes causes fever, seizures, and serious long-term movement problems. In 1944, the war in the Pacific was heating up and the U.S. Army wanted a vaccine that would protect soldiers. Hilleman offered to make the vaccine for $3 a dose and he won the contract. Squibb gave him a horse barn and an engineer. An old farm boy, he bulldozed out the manure, painted the floor, and went to work. From his U. of Chicago days, Hilleman knew the encephalitis virus would grow in the brain of a mouse. As he later explained to fellow “vaccinologist” Burt Dorman, making a vaccine is like getting the old tractor working. You fiddle with it. If that doesn’t work, you fiddle with it some more. Hilleman figured out how to create the vaccine and assembled a crew of 30 women. They injected the virus into the skulls of mice and waited for it to grow. After a few days, they killed the rodents with ether and “harvested 30,000 brains a day.” The organs were homogenized with a blender, washed, centrifuged, and washed again and again. The process was repeated until the solution contained pure viruses. Then the infectious agents were inactivated with formaldehyde. Three months later, Squibb had enough vaccine to immunize 200,000 troops.

After the Second World War, the U.S. military and the World Health Organization were always on the lookout for the next influenza pandemic. In 1957, Hilleman was working at Walter Reed military hospital and he read about a flu outbreak in Hong Kong. It infected 10 percent of the population—250,000 people—so it was worrisome. He contacted an army physician in Japan and the doctor got an infected navy serviceman to gargle and spit into a cup. A month later, the specimen arrived in D.C. and Hilleman put the spit into a fertilized egg. Then he watched the flu virus grow and developed a way to test for the presence of antibodies to the germ. He checked the serum of hundreds of people and found that very few living humans had been exposed to anything like this virus. The only people who had antibodies were 70 and 80 year olds who had survived the flu epidemic of 1889–90.

Hilleman figured that a virus would arrive in the fall and create a devastating epidemic, and he “sent out a press release and warned the world” but no one seemed to believe him. “Joe Bell,” a prominent U.S. Public Health Service epidemiologist known for his attention to detail, commented, “What pandemic? What Influenza?” “How,” Hilleman wondered, “could people live in this world and be so stupid.” Eventually, Hilleman went to a restaurant where the head of the U.S. influenza commission was eating. He interrupted the man’s meal, showed him the information, and told him that ignoring his findings was “a big mistake.” The commissioner checked the data and agreed. It was a pandemic virus.

Hilleman contacted six companies that produced flu vaccine. He cut the red tape, sidestepped a few rules, and told chicken growers NOT to kill roosters. As a farmer, he knew roosters were usually killed late in the hatching season and companies would need a lot of fertilized eggs. By late fall, 40 million doses of vaccine were available and many people were immunized. The disease arrived in the U.S. that September in the body of a girl who attended a church conference in Grinnell, Iowa, and in the lungs of Boy Scouts from Hawaii who attended a jamboree at Valley Forge, Pennsylvania. The 1957 flu killed 70,000 Americans and 4 million worldwide, but thousands of lives were saved.

In the 1950s, Hilleman moved to the Merck Company and started a revolution of sorts. Over the years, his group turned out products that prevented a staggering 40 animal and human diseases. (Paul Offit M.D., a professor of pediatrics detailed Hillman’s story in his excellent book Vaccinated.)

The vaccines for measles, mumps, and chicken pox became available in the late ’60s and early ’70s. In 1957, the year before I graduated from med school, the people I interviewed all remembered their childhood illnesses, staying home for a week, fevers, rash, and a swollen jaw.

Baruch Blumberg was the son of a lawyer who struggled during the Great Depression. He was 16 when the Japanese bombed Pearl Harbor and he joined the navy and became a midshipman. When the war ended, he used the G.I. Bill to pay for his schooling and planned to study math. But his father, who usually didn’t say much, said, “I think you should go to medical school,” and he said OK. He met his future wife, Jean, when he was a medical intern at Bellevue hospital. She worked in the hospital research lab and their dates were dinners in the hospital cafeteria and strolls through the streets of New York. “A child of the depression,” Blumberg was paid $25 a week and managed to save most of the money. He became a researcher, and in the days before we knew how to access DNA, he tried to classify genes by the presence of certain unique proteins in a person’s blood. (Many genes direct cells to make a specific protein.)

One of the oddball proteins he discovered clearly couldn’t be genetic in origin. He found it in an Australian Aborigine, and it was also present in the blood of a New Yorker. The American had hemophilia and had been transfused many times. There was no way the two could have a unique genetic connection. Over the years, Blumberg studied the protein and learned it was part of the shell of the hepatitis B virus. When the virus replicates it is overproduced, and it spills into the blood.

When the protein was present in a person’s blood, it indicated an active infection. When it was absent and the blood contained an antibody to hepatitis B, it meant the individual had been infected but was now immune.

Maurice Hilleman used the surface antigen and developed a vaccine. He was unable to completely eradicate the virus from the blood, so he treated the preparation with formaldehyde, pepsin, and urea. That should have killed any virus that was present. To convince the public it was safe, he asked Merck mid-level executives to be the first to be injected. As Hilleman later quipped, “We found the most worthless people we could find in the world who would be least likely to sue.”

No one volunteered so he gathered the execs and explained that “No” was not an option. Fearing the vaccine might have been contaminated with HIV, some of the executives who were injected later admitted they took the shot but were “scared to death.”

When he later learned the vaccine production was being accelerated, Hilleman met with the people making it. His killing process was effective, but it was slow. Hilleman assumed steps were being skipped and no one knew if it affected the vaccine’s safety. He told the production crew he suspected someone was “changing the fucking process so he can get more yield and earn a bonus. Meatheads are everywhere.”

The world needed a safe and effective hepatitis B vaccine. The virus was present, though usually inactive, in the livers of over 200 million people in the world.  Approximately 1.2 million were Americans. But people feared the Hilleman vaccine and didn’t take it.

In the process of making his vaccine Hillman had demonstrated that it was probably possible to use the outer shell of a virus to make a vaccine and Bill Rutter took notice. In the late 1960s, Rutter decided to try to use genetic engineering to make the membrane that surrounds the virus.  If he was successful, scientists could use the protein to develop a vaccine that people wouldn’t be afraid to use.

Rutter was the chief of biochemistry at the University of California in San Francisco. He was the son of a British Quaker and was born and raised in Malad, a small town in southern Idaho. His grandfather had been a British Army officer in India and had told young William about the poverty and exotic parasitic diseases he had witnessed. After hearing the stories, young William thought he would someday go to the school of tropical medicine in Calcutta.

During the Second World War, Rutter lied about his age, and when he was 16 he joined the navy. When the war ended, he went to Harvard and was drawn to science. He was accepted to Harvard medical school, but after he attended a few medical school classes with a cousin, he realized he wanted to be a scientist. He earned a PhD at the University of Illinois and spent a decade as a researcher and professor at the University of Illinois, Stanford, and the University of Washington.

In 1968, after refusing the job offer three times, he became the chief of the biochemistry department at the University of California in San Francisco. The unit had been leaderless for six years and (he once quipped) “every good scientist in the United States had probably been asked to take that job and turned it down.” He claimed he accepted the post because twenty faculty positions were open, and that was a “bonanza for recruiting.”In academia, investigators don’t always cooperate and share. Rutter knew science was competitive. “Everyone is trying to beat you and will use every trick in the book. You try to cover your bets in many different ways.” Rutter gathered top-notch researchers and got them to work collaboratively. In his department, associates shared their knowledge.

Herbert Boyer was a researcher at UCSF when Rutter was chief. Boyer teamed up with Stanley Cohen, a Stanford researcher.  Together they learned how to insert genes into plasmids (circular collections of double stranded DNA that are found outside the nucleus--in the cytoplasm of some bacteria and cells.).  When a gene, a specific length of DNA, was placed in a plasmid and planted in a bacterium,  the cell produced a specific protein. Boyer shared his knowledge with Rutter before Boyer left the university of California and helped create Genentech.

The idea of using implanted genes to make proteins frightened some politicians. “Some portion of scientists was genuinely concerned. Others enjoyed the debate and the public controversy.”

There was a Senate hearing on the topic of genetic engineering and Rutter attended. Margaret Mead arrived wearing a huge long robe and carrying a shepherd’s staff. “Adlai Stevenson, a Senator and a lawyer who would later run for the presidency of the U.S., ran the proceeding. He introduced Margaret Mead as a world-renowned scientist who could give guidance on these issues.” Mead was an anthropologist who became famous after she spent nine months in Samoa. She learned that “adolescence on the island was not a stressful time for girls because their cultural patterns were different than those in the U.S.”

At the hearing she stood and repeatedly said something like, “You’re going to hear today from these scientists that this (genetic engineering) is not dangerous. I’m here to tell you it is dangerous.” After each repetition of her statement, she pounded the floor with her staff for emphasis. “Boom! Boom!”. To Rutter, “a social anthropologist with her shepherd’s staff giving advice on molecular, microbiological, and physiological science” was troubling. Observing the theatrics and attitudes, Rutter realized that if he wanted to make the hepatitis B vaccine his way, he would have to give up his job as chief of biochemistry and go private. In 1981, Rutter acquired venture funding, hired great researchers, and formed Chiron. “It was not an issue of damn the torpedoes, full speed ahead.” The business of the company initially was research, pure and simple—understanding the potential of a set of technologies. The major pharmaceutical companies didn’t want to become polluted by something that was “controversial” like genetic engineering, and they stayed on the sidelines.

Merck gave Rutter’s group the genome--hepatitis B DNA and one of Chiron founders, Pablo Valenzuela, isolated the section of the viral genome that coded (was the blueprint) for the outer membrane of the hepatitis B virus.  The Chiron team inserted that DNA into a plasmid and put the plasmid into yeast.  The organism made significant amounts of Hepatitis B surface antigen. When the particles were injected into people, their bodies produced antibodies that attacked the outer membrane of the virus, and the vaccine prevented hepatitis B.  It was the first effective human vaccine made of viral sub-units but it was not the last.  

By the 1990s, pharmaceutical companies had largely stopped using formaldehyde-inactivated viruses, and the immunizations they made were “technologically more sophisticated and substantially more expensive.  Takeda in Japan used envelope proteins to make a 9-valent human papilloma virus vaccine. Papilloma is a viral infection that dramatically increases the future risk of cancer of the cervix. The vaccine is given to girls before they become sexually active.  (See section on childbirth.) 

For decades, insurance policies covered the costs of none, some, or all of the charges for new vaccines. Then the Affordable Care Act was passed, and on September 23, 2010, the president made it official. “Preventive services that have strong scientific evidence of their health benefits must be covered and plans can no longer charge a patient a copayment, co-insurance or deductible for these services when they are delivered by a network provider.”

An advisory committee of the Centers for Disease Control published a list of 20 vaccine-specific recommendations for conditions ranging from rabies to smallpox.

In 2020, a novel, sometimes lethal, coronavirus kicked off an epidemic, and by June 2020, according to the website MarketWatch, nine pharmaceutical companies were racing to develop a vaccine that stimulates the body to develop antibodies to part of the viral shell. Millions of dollars were being advanced by the government, and investors, hoping to make a lot of money, were buying the stock of vaccine makers.

Shortly after the virus started ravaging China, researchers determined the sequence of nucleotides that led to the formation of the infectious agent. A section of the RNA was the blueprint for the spike proteins that speckle the wall of the coronavirus. The spike connects the virus to the cell it is going to invade. COVID is an RNA virus. Investigators learned how to transform a slice of viral RNA into a piece of messenger RNA. They used their knowledge to construct spike-specific messenger RNA, and they “packaged” the new RNA.  When it was injected into a person, it entered cells and the RNA forced the cells to make spike proteins. The body’s immune system recognized the new proteins and realized they were foreign antigens. Lymphocytes made antibodies.  In studies in humans MRNA prevented or modified Covid infections.  As opposed to the production of attenuated or inactivated viruses, the production of mRNA vaccines can take only days or weeks.”

Upon entering cells, unmodified in vitro translated mRNA becomes intrinsically immunogenic.

Pseudo-uridine is a naturally occurring modified nucleotide that is also highly abundant and naturally widespread in virtually all RNAs of all cells.  Karikó et al. found that using pseudo-uridine in place of uridine when creating in vitro translated mRNA, allowed them to create a chain of nucleotides that suppresses the immune response.

Current mRNA vaccines are protected by lipid nano-particle cells until the reach the site of action.  The lipids ultimately carry their cargo to the lymph nodes and are internalized by dendritic cells.

Both Pfizer-BioNTech and Moderna Therapeutics COVID-19 spike-encoding mRNA vaccines (both with more than 90% of efficacy against COVID-19 symptoms) contain modified pseudo-uridines).

A study suggested pseudo-uridine modified mRNA has increased translatability and “N1-Methylated pseudo-uridine behaves better than uridine. 

In 2020, Pfizer-BioNTech added N1-methyl-Ψto their COVID-19 mRNA MERS vaccine candidate and gained knowledge they later used when developing the COVID-19 mRNA vaccine.

Other vaccines were developed and are effective.

 Johnson and Johnson produced a vaccine using an adenovirus to carry the spike protein DNA into cells.  Non-replicating vector vaccines are unable to make new viral particles; they only produce the vaccine antigen. once injected into the body, these vaccine viruses begin infecting cells and inserting their genetic material – including the antigen gene – into the cells’ nuclei. Human cells manufacture the antigen as if it were one of their own proteins and this is presented on their surface alongside many other proteins. When the immune cells detect the foreign antigen, they mount an immune response against it. Unfortunately some people had previously have been exposed to the virus vector and had an immune response.  That reduced the effectiveness of the vaccine.  Also vaccine production is difficult to do on a large scale. .

Sinopharm, a Chinese and Bharat Biotech, an Indian company each developed a whole virus vaccine and got emergency WHO authorization to use the product.  Each used a weakened or deactivated version of the disease-causing virus to trigger protective immunity against it.  

Nucleic acid vaccines use genetic material from a disease-causing virus to trigger protective immunity against it.  Novavax developed a protein subunit vaccine called Nuvaxovid.  It was approved by the FDA.

President Trump claims credit for the U.S. program that led to the end of the epidemic-- the program called “warp speed.”  He said he took the vaccine.  Clearly the search for, creation of, and distribution of the vaccine began when he was president.    

Researchers have been unable to make a vaccine that prevents HIV.  Within 2 to 3 days after a person is infected with HIV a few of the RNA viruses have already entered a T lymphocyte.  They have created DNA copies of themselves and the DNA has become a gene.  Much as a newly hatched queen bee stings and destroys her un-hatched contenders, a kind of natural selection allows one clone of viruses to take charge.  The enzyme the viruses uses to make DNA copies of the RNA,(reverse transcriptase) is error prone.  When viruses make DNA copies they make mistakes.  At least one DNA base pair is incorrect and the virus that’s created is a mutant. When infected people make antibodies, their immune systems can’t keep up with the viral alterations, and most HIV antibodies are not protective. (A rare person eventually makes broadly neutralizing antibodies. They are active against a wide variety of different viral strains, and they are able to control the HIV infection.)  The drugs that fight HIV don’t cure the disease because they are unable to kill the occasional infected cell that is inactive, but that wake up when people stop taking antiviral drugs. 

 

It’s hard to quantitate the effect that vaccines and childhood illnesses have on our pocket books and lives, but a measles outbreak in Africa a few years ago provides a little insight.  It affected 64,000 kids and killed a thousand.  Overall, according to the United Nations, vaccines have lowered African measles deaths in children under five years old from 733,000 in 2000 to 118,000 in 2008.  

The stories in the blog were part of two books by Steve Fredman: 

1.  The Troubled Health Care Dollar

2.  Understanding Modern Health Care  The wonders we created and the Potholes we dug.

The history of the polio vaccines appears in a separate chapter of this blog and is titled The polio vaccine debate. 

In December 2024 president elect Donald Trump “held a wide-ranging news conference in which he said he would preserve access to the polio vaccine but equivocated on other vaccines,

“Trump defended his choice for health secretary, prominent vaccine skeptic Robert F. Kennedy Jr., but said he personally is a “big believer” in the polio vaccine and would preserve access to it.  Kennedy has long advanced the debunked idea that vaccines cause autism. Trump seemed to question whether there’s a link, saying “We’re looking to find out,” and remarked on the rising cases of autism being diagnosed.” “There’s something wrong, and we’re going to find out about it,” he said.”

https://apnews.com/article/trump-news-conference-takeaways-d2eecc2a57652976a0835cdd1d1a50f6

In 2017 during the development of mRNA vaccine against Zika virus, N1-methyl-pseudouridine was used and incorporated into two similar mRNA vaccines encoding Zika virus surface proteins. The modified mRNA, encapsulated in liquid nanoparticles, was designed and then tested to protect against the Zika virus in human cells, mice, and non-human primates. In the following year, further success was obtained with N1-methyl-Ψ-modified mRNA vaccines against HIV-1, Zika, and influenza virus, achieving a sustained antibody response in a preclinical setting.  A similar example was presented against the Ebola virus.