Vaccine Memories: From Polio to Autism

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Salk_Thank_You“April 15 – Polio Vaccine Perfected!!!!”

So wrote my mother in 1955, on the “Baby’s Health Record” page of my baby book. I unearthed it a few days ago while looking for some old writing clips.

Just a day earlier, I’d just reported in Medscape on a study finding that adding injected Salk polio vaccine to the oral Sabin vaccine series can boost immunity in parts of the world where polio is still endemic, such as Nigeria, Pakistan, and Afghanistan.

The coincidences continued.

THE SUMMERTIME NIGHTMARE OF POLIO

Herd immunity protects a population against an infectious disease when enough individuals are vaccinated to block spread of the pathogen.

Herd immunity protects a population against an infectious disease when enough individuals are vaccinated to block spread of the pathogen.

Among my old article clips I soon found “Polio Eradication  Goal Extended,” in The Scientist from 2000, which had been the target year for ending polio. I’d quoted U.S. Secretary of Health and Human Services Donna Shalala defining herd immunity on a global scale: “No nation is truly free from polio unless every nation is free of polio.”

It’s a message that needs repeating, for a number of infectious diseases.

My Scientist article began with a glimpse of the pre-polio-vaccine days:

An iron lung took over for the flaccid chest muscles of people with polio.

An iron lung took over for the flaccid chest muscles of people with polio.

For parents of young children in the early 1950s, summertime brought the terror of a fever that might explode into ‘infantile paralysis,’ a fear propelled by images of Franklin D. Roosevelt’s battle with the disease. Although only 1 percent of infected individuals developed severe symptoms as the virus invaded spinal cord cells, the number of cases grew large enough to inspire a massive effort to develop a vaccine, including the founding of the March of Dimes in 1938 to specifically battle polio.

For those old enough to remember the Beatles, polio vaccines were part of childhood. By 1955, youngsters in many nations received injections of Jonas Salk’s inactivated polio vaccine. By 1962, children were lining up at school, tongues out to receive pink-stained lumps of sugar impregnated with Albert Sabin’s live, attenuated oral polio vaccine.”

Neither Salk nor Sabin sought patent protection for their inventions, which offer the best protection when teamed. The first vaccine, live but weakened, was actually invented in 1948 by virologist Hilary Koprowski, director of the Wistar Institute in Philadelphia for 30 years. He died last year.

Kathleen Sebelius gives oral polio vaccine to a child in India.

Kathleen Sebelius gives oral polio vaccine to a child in India.

Sabin’s oral vaccine, much more acceptable to the kindergarten set than a shot in the arm, sent attenuated virus directly into the gastrointestinal tract. To develop the oral vaccine, passage through several non-human animal hosts weakened the virus so that it activated immunity in people without causing disease.

Stool from kids who ate the sugar cubes released the weakened poliovirus into sewage, spreading protection even to those who hadn’t been vaccinated, like older people. But the virus can mutate, as live viruses do, sometimes into a form that invades nerve cells. Very very rarely, this causes the acute flaccid paralysis of poliomyelitis.

baby bookTHE “CHILDHOOD DISEASES”
My sister Edith had the good sense to be born after me, and even though that meant she was a mere penciled-in footnote in my baby book, she had some vaccines for which I suffered through the associated illnesses. We straddled that time when the classic illnesses of childhood began to go away.

When I was 3 I had the measles for a full month. During a house call, the pediatrician prepared my parents for the chance that I might need to be hospitalized, and possibly lose my hearing or end up brain damaged. Fortunately I recovered.

A few years later I watched several people hold down a screaming Edith as she got the new measles vaccine, 2 shots back then. But we both had mumps, chickenpox, and German measles, their vaccines not yet perfected. She reports recalling her delight at expecting a shot and getting a sugar cube.

Because smallpox vaccine was initially derived from cowpox lesions, people feared the vaccine would cause tiny bovines to emerge from the skin. This famous cartoon is from 1802.

Because smallpox vaccine was initially derived from cowpox lesions, people feared the vaccine would cause tiny bovines to emerge from the skin. This famous cartoon is from 1802.

According to my baby book, my smallpox vaccine of April 5, 1955, didn’t take, so I had it again on May 6. Now we don’t hear much about smallpox unless it’s discovered in a back room at a government lab.

May 6, 1955 must have been a bad day for me (and my mother), because I had my first whooping cough (pertussis) vaccine then too, and again a month later. Edith had to have pertussis vaccine again just last week because she’s visiting her about–to-be-born first grandchild in California, where the disease has returned due both to natural waning of the immune response and to people who won’t vaccinate their children. Pertussis can kill a baby.

During my first year I also had 4 diphtheria shots and 1 for tetanus, the DPT vaccine, now called Tdap, yet to have been combined into existence. It is the main target of the anti-vaccine movement.

Thanks, mom, for getting me vaccinated.

Thanks, mom, for getting me vaccinated.

I had my polio vaccine shots in May, June, and October of 1956. Being a toddler, I didn’t know that the vaccine had run into trouble right out of the gate. Thirteen days after its debut in April 1955, the product from Cutter Labs in Berkeley, California, was found to harbor live virus, which infected 94 vaccinated kids and 166 of their close contacts. On May 7, the Surgeon General suspended the polio vaccine program, spearheading government vaccine surveillance. Polio vaccinations resumed in the fall of 1955, much to the relief of millions of parents.

My mother, back in 1955, understood the concept of herd immunity, if not by that name. Grateful and relieved parents throughout the U.S. realized that if enough people were vaccinated, active virus would have nowhere to infect, and polio would go away.

An alternate possible explanation for the rise in autism cases: extended use of folic acid in pregnancy.

An alternate possible explanation for the rise in autism cases: extended use of folic acid in pregnancy.

AUTISM AND FOLIC ACID
I hated vaccines because they hurt, but even as a small child wondered how they worked. And because some of my earliest memories are of those first vaccines, I signed on as this year’s keynote speaker for the  March of Dimes student convocation when I learned that the first speaker, in 1971, was Jonas Salk.

At the last talk in the series, at the Institute for Basic Research in Staten Island, Mohammed Junaid, PhD, head of the structural neurobiology lab there, talked to the high school students just before I did. His team’s data may explain the increase in incidence of autism: folic acid supplementation extending well beyond day 28 of gestation, when it prevents neural tube defects (NTDs). So far they’ve got an association (timing) and a possible mechanism (epigenetics). The vaccine connection, of course, is the blame for the uptick in autism cases.

Folic acid

Folic acid

In 1992, the CDC recommended that pregnant women get .4 mg of folic acid daily to prevent NTDs, and in 1998, the US government mandated adding folic acid to grains and cereals to help them do so. (The folate form in foods is poorly absorbed.) But getting this much folic acid from even fortified foods isn’t that easy, so in 2003, clinical management guidelines  from the American College of Obstetricians and Gynecologists called for folic acid in pill form for pregnant women.

Through the 1990s, recommendations stressed folic acid during the perinatal period – a month before conception and 2 to 3 months after. But somehow, perhaps following a more-is-better philosophy, the time to take folic acid supplements during pregnancy stretched. Some women even continue to take the leftovers after giving birth, perhaps reassured by studies countering concerns that the vitamin might cause heart problems, twinning, allergies, and mask B12 deficiency.

Advised WebMD: “The CDC recommends that you start taking folic acid every day for at least a month before you become pregnant, and every day while you are pregnant. However, the CDC also recommends that all women of childbearing age take folic acid every day. So you’d be fine to start taking it even earlier.”

But is it “fine” to continue taking a high dose of folic acid beyond the point at which the neural tube closes?

Might exposure during the second and third trimesters, when brain development accelerates, lead to more subtle symptoms than the open neural tube that early exposure prevents? Like behavioral ones? It makes sense, because folic acid begins the pathway that adds methyl groups to certain genes, silencing their expression – a great example of an epigenetic effect.

Autism enters the picture rather circuitously.

A widely-reported 2013 study presented evidence that folic acid taken from 4 weeks before to 8 weeks after giving birth lowers incidence of autism. Less widely-reported was a study from two years earlier, from Dr. Junaid and his colleagues, who used white blood cells and animal models to look at what happens later in gestation, mimicking the situation of women who continue to take higher doses of the vitamin throughout pregnancy.

Methylation silences genes.

Methylation silences genes.

Indeed, the experiments showed that exposure to high doses of folic acid past the first trimester causes overexpression of a whole bunch of genes. The list includes XIST, the site that controls methylation (silencing) of one entire X chromosome. This might explain why boys with autism outnumber girls. Males are more vulnerable to the effects of both mutation and epigenetic changes because they only have one X chromosome, and are in this genetic sense the weaker sex. Also underexpressed in the presence of folic acid is the FMR1 gene, which lies behind fragile X syndrome, a common cause of autism.

I’d scribbled notes at Dr. Junaid’s talk in April and read the group’s papers, waiting to blog about the work until the results he discussed were published. That happened, also coincidentally, on the day that I found my baby book nestled among my tattered writing clips.

Dr. Junaid’s group reported in PLoS One last week that prolonged prenatal exposure to folic acid in mice is associated with anxiety, hyperactivity, and increased vocalization, but with no effects on learning memory, or social behavior. Male mice were more likely to respond to the excess than female mice. And they identified nine key genes with altered expression. Not exactly autism, but distinct brain changes nonetheless.

The team is conservative in their conclusion that there may be a “loss of benefit” to prolonged folic acid supplementation, writing: “Unregulated high FA supplementation during pregnancy and throughout the life course may have lasting effects, with alterations in brain development resulting in changes in behavior.”

The increase in number of autism cases parallels folic acid use during pregnancy. Coincidence?

Clearly much more work needs to be done on the link, if any, between extended folic acid supplementation and autism. But IMHO this is the very best type of scientific investigation.

It isn’t a “cure” or a “breakthrough” or even “proof,” which are to me the “F” words of reporting on science. The link isn’t coming from celebrities who speak as if they’ve anointed themselves with PhDs in immunology. The work of Dr. Junaid and his colleagues presents a compelling idea, providing enough information to seed a new hypothesis: Can overexposure to folic acid in the second and third trimesters of pregnancy increase risk of developing autism?

That’s what science is: framing new questions.

PikiWiki_Israel_10876_Alyn_Day_CampSo stay tuned. We aren’t nearly done “rounding up the suspects” in causing autism, but meanwhile vaccine phobia is opening the door to the diseases I had as a child, and some much worse.

Do we really want to return to those long-ago summers when parents feared their kids would spike fevers and become paralyzed in a matter of days?

(Thanks to Wikimedia for images and to my mother for my baby book — and getting me vaccinated.)

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