Discovery of the Virus Occurred in Two Major Steps 

Hepatitis was suspected to have a viral etiology by the first decade of the 20th century, and by World War II, physicians were giving gamma globulin to mitigate outbreaks. Generalized immune globulin lacks the specificity of hepatitis B Ig (HBIG) administered today to high-risk neonates along with the birth dose of hepatitis B virus (HBV) vaccine, but it helped prevent the disease from spreading in the close quarters common in military settings. On an episode of the period TV series M*A*S*H, set in wartime Korea, the lead character, Hawkeye Pierce, administers intramuscular gamma globulin injections as prophylaxis for “hepatitis.” The program did not specify A, B, or C, because in the 1950s liver inflammation was classified into just two types: infectious hepatitis, which spreads via the fecal-oral route, and a serum, or blood-borne, form of the illness.

The classification changed with the identification of HBV in the 1960s, which occurred in two major steps, each involving a different researcher. While working at the US National Institutes of Health, Baruch “Barry” Blumberg discovered a protein in blood that he named “Australia antigen” in 1963, because initially it turned up only in the serum of an Aboriginal Australian. Blumberg, who had been interested in what he called “geographic medicine,” believed this protein to be human, not viral, until it later showed up in the blood of people from various other geographic locations, all of them recipients of multiple transfusions. But it took the second researcher, Alfred Prince, to show that the Australia antigen was a piece of a virus that spread in the blood.

“Prince concluded that the Australia antigen was located on a virus particle and that the virus particle was etiologically related to some or all cases of ‘serum hepatitis,’ later called hepatitis B virus (HBV),” said Paul A. Offit, MD, professor of pediatrics in the Division of Infectious Diseases at Children’s Hospital of Philadelphia, Philadelphia. Since the protein was on, rather than inside, the virus, it became known as the HBV surface antigen (HBsAg), the same protein used in today’s recombinant HBV vaccine. Since it is also the primary marker for active HBV infection, Blumberg and another researcher, Irving Millman, used it as the basis for the HBV screening test that remains the standard assay.

Early HBV Vaccines Came From Infected People

The development of a vaccine against HBV began when Blumberg and Millman took serum from people with chronic infection and heat-treated the samples to inactivate the pathogen while preserving its HBsAg immunogenicity. This rudimentary vaccine was administered to humans in limited experimental settings, including, notoriously, one at the Willowbrook State School, Staten Island, New York (more on that story in a moment). But a commercialized HBV vaccine for widespread use came from Merck & Co., Inc., and its veteran vaccine maker, Maurice Hilleman, who has developed more vaccines than anyone else in history (more than 40).

Like the Blumberg/Millman prototype, Merck’s first version of the HBV vaccine, Heptavax-B, which began widespread distribution in early 1982, was also derived from the blood of humans with chronic HBV infection. The approach was called a “plasma drive” vaccine, which sounds rather scary, yet Hillman’s technique for inactivating the virus and purifying the samples made it quite safe, with no evidence of HBV infection from the vaccine. Meanwhile, the efficacy was calculated at 99.99%.

Hillman was able to take blood generally from men who had sex with men in New York City who also were susceptible to hepatitis B, then he basically purified hepatitis B surface antigen, then treated that product with pepsin, urea, and formaldehyde, Offit said, and noted that the vaccine was 99% pure HBsAg. “He then published a series of papers showing that that would kill any human virus,” Offit said. “I’d argue that was the safest vaccine made from the most dangerous starting material.”

That year was also when concerns first emerged that HIV might contaminate human blood. In 1984, as the AIDS epidemic worsened and its viral cause was identified, Hilleman’s human serum vaccine started to worry researchers. This led him, Merck, and the FDA to replace Heptavax-B with a recombinant vaccine, Recombivax HB, in 1986.

The ‘Pediatric Tuskegee’

From the experience in World War II and Korea, mid-century medicine knew well enough that gamma globulin helped fight whatever pathogen caused hepatitis. But this didn’t stop the Willowbrook State School from deliberately infecting some 700 mentally disabled children with serum hepatitis and infectious hepatitis to confirm the benefits of gamma globulin and to track the progression of the disease in the years 1956-1971. Directed by infectious disease researcher Saul Krugman, the program also later tested the Blumberg/Millman vaccine prototype on children at the school.

While remembered as the “Pediatric Tuskegee” in reference to the infamous Tuskegee experiments on syphilis, studies at facilities like Willowbrook were not as unusual for that era as we might assume.

“Not in defense of Saul Krugman, but a lot of those early studies were done in institutions for the mentally disabled,” Offit said. “Today, we think it’s abhorrent, but the reasoning of the time was not so much that they were the most expendable members of society but the most vulnerable members of society, because the places were hellholes with poor sanitation.”

The Birth Dose Is Beneficial, Even When the Mother Tests Negative for HBV

Approximately 90% of neonates who acquire HBV infection will develop chronic, lifelong infection, putting them at high risk for cirrhosis and hepatocellular carcinoma. The World Health Organization (WHO), the American Academy of Pediatrics, and, until recently, the CDC have recommended the first dose of HBV vaccine be administered within 24 hours of birth. Guidelines call for infants at high risk — a category that covers maternal infection or unknown status, preterm birth, and perinatal exposure to the virus — to receive HBIG along with the vaccine dose, but the vaccine dose itself at birth is recommended for all neonates.

The rationale for this guidance stems from a combination of factors, including that a mother can become infected subsequent to being tested and that she or other caretakers can infect the child after birth. HBV spreads easily; children can get it from towels, toothbrushes, nail clippers, and any casual contact. What’s more, the screening test can be falsely negative, and mistakes happen in taking blood samples and ordering tests that can also disrupt screening. But the strongest case comes from the statistics themselves.

“In the years 1982 to 1991, when the HBV vaccine was recommended as a birth dose, first only in neonates whose mothers screened positive for HBsAg, then also in those whose mothers were high risk regardless of HBsAg status, we didn’t really make a dent in the infection rate in children under age 10,” Offit said. “So, in 1991 they went to a universal birth dose, and with that dose we essentially eliminated HBV in the under 10-year-olds.”

Considering Guinea-Bissau from this perspective, the numbers also speak volumes. Lacking the resources to implement the WHO-recommended birth dose of HBV vaccine, clinicians in that country have instead been giving the first dose at 6 weeks of age. The results are stark: More than 18% of the population, including 11% of children younger than 18 months, have HBV. This figure is roughly triple the average rate in sub-Saharan Africa as a whole.

In response, Guinea-Bissau was planning to begin implementing the proper WHO birth dose on the day of birth, starting in 2027. But RFK Jr, who believes the birth dose causes neurodevelopmental delays and increased mortality and claims it to be a “likely culprit” of autism, has seen Guinea-Bissau as an opportunity to test his hypothesis.

“He contracted with Guinea-Bissau to run a controlled experiment on 14,000 neonates, giving 7000 the birth dose and the other 7000 will get the dose at 6 weeks of age, to see if he’s right about the damage,” Offit said of Kennedy. “This is in a country with an HBV rate of 18%.”

Will RFK Jr get his way? Offit implied he thinks the trial may well fail the ethical review, given how the “control group” — the 7000 babies who would receive the later dose — would be at extreme risk for getting infected with HBV and thus at risk for chronic infection.