“Is public health becoming illiberal?,” asked Katelyn Jetelina last week. I assumed it would be a classic case of Betteridge’s Law &ndash…
This is the last post in a series highlighting outstanding women in vaccine science or immunology related to vaccine development in the 20th century. And there are some milestones for women in immunology more generally, too. The odds have historically been dramatically stacked against women gaining access to science education and research careers, though, and if they did get through, against getting credit for their contributions – and then against being celebrated, too. All of which makes those who did achieve important breakthroughs and prominence all the more impressive.
1970: PhD student Eva Engvall developed ELISA – the enzyme-linked immunosorbent assay – a much simpler and cheaper test to identify antigens and antibodies
Eva Engvall was born in 1940 in Sweden. But I couldn’t find anything about her life before her major scientific discovery. Engvall was a doctoral student at the University of Stockholm, with Peter Perlmann. In part 2 of this series, I wrote about Rosalyn Sussman Yalow, who was awarded the Nobel Prize for co-developing the radioimmunoassay (RIA). Engvall explains why developing a new technique was her doctoral project: “At the time, RIAs were in full bloom, but they were too sophisticated for many areas of research and diagnosis because they required expensive equipment and used antigens and antibodies labeled with radioactive isotopes with short half-lives. We wanted something simpler with the same sensitivity”.
Enzymes had been used to label antibodies in chemistry before, and so they thought it was worth trying for blood tests. The test uses antibodies to find hormones and viruses, and its use in medicine and research is massive – including uses as diverse as pregnancy tests and vaccine research.
Naming it ELISA was “an important decision”, she wrote. It’s an acronym for Enzyme-Linked ImmunoSorbent Assay. They had the first proof-of-concept results ready in 1970, but had trouble getting it published. The paper was published in 1971. Her dissertation followed in 1975. Independently, researchers in the Netherlands were working on the same idea, and they published the results of their test, called EIA, in 1971 as well. The Dutch group patented their test, but Engvall and Perlmann didn’t. (That meant Engvall never made money from her innovation – she told an NPR interviewer in 2006, that her husband, Finnish cancer researcher Erkki Ruoslahti, made money out of biotech, enabling them to live on a 1,100-acre ranch in California.)
Engvall moved to California to work in an institute there in 1979, continuing to work on antibodies, especially monoclonal antibodies. She and her colleagues identified defects in a protein, merosin, as a cause of muscular dystrophy, and mutation in another protein, fibrillin, as a factor in Marfan Syndrome.
1975: Eva Klein and colleagues publish the results of work she initiated describing a type of previously unknown lymphocyte – she called them “natural killer cells”
Eva Klein (née Fischer) was born in 1925 – she turned 90 in 2015, and amongst other things, she was translating Hungarian poetry into Swedish. She was born in Budapest, in a well-to-do Jewish family. She went to private school, and was into sport and theatre as well as science, inspired by Marie Curie, interested in both theatre and medicine as possible careers. But her choices and life were severely constrained by worsening anti-semitism and persecution – Germany occupied Hungary after she finished high school.
Klein studied medicine at the University of Budapest. She and several members of her family escaped the Holocaust by hiding in 1944/1945 inside the University, helped by János Szirmai, who was helping other Jewish people survive as well. He forged documents for them, for example. He was a former seminary student who left the path to priesthood when he fell in love with a nun and married. Szirmai was a bookbinder who studied books, born in then-Czechoslovakia. After the war, he moved to the Netherlands and studied medicine. In 2006, he was honored as by Yad Vashem.
Eva married another medical student, George Klein (1925-2016). Together, they would lay some of the foundations of cancer immunology. They left Hungary in 1947, settling in Sweden. They both worked while they finished their medical degrees at the Karolinska Institute, and then spent their careers there. Eva was tenured in 1979.
The Kleins did a range of research on cancer cells and how genes in normal cells can suppress them, both together and separately. Eva studied viruses as well as immunology. In the 1960s, she developed cell lines from Burkitt’s lymphoma that are still used. In the 1970s, the group was studying the link between lymphocytes and anti-tumor response. Eva pursued an idea she had that the others didn’t see as critical. She worked on it with 3 students and another professor. They identified a type of lymphocyte (white cell) that is cytotoxic – they could destroy cancerous cells and cells infected with viruses. She called them “natural killer cells”. They published their findings in 1975. Stimulating natural killer cells is one of the ways that HPV vaccine works, for example.
Klein became a member of the Royal Swedish Academy of Sciences in 1987, and the Hungarian Academy of Sciences in 1993. She was awarded the Karolinska’s Silver Medal in 2010. In 2013, she was elected to a Fellowship of the American Association for Cancer Research Academy. In 2005, the Karolinska established the Georg and Eva Klein Foundation.
1983: Philippa Marrack and colleagues isolated T-cell antigen receptors – they enable T-cells to recognize and respond to antigens
Philippa Marrack was born in Ewell, south of London, in 1945. Her father was a Naval officer, and her paternal grandfather was a mathematician, and his brother was John Marrack, a prominent immunologist and founding editor of the British Society for Immunology’s journal, Immunology. He wasn’t part of her family’s life, though she did meet him several times as an adult.
The family moved many times, including internationally, and she had lived in 20 houses by the time she was 20. Of the 8 schools she attended, 2 were boarding schools. Marrack studied biology at Cambridge University in New Hall, gaining her PhD in 1970. She studied T-cells for her doctorate because her advisor wanted his lab to get into the area, and liked the idea of having a Marrack working on a topic John Marrack was known for. While she was at Cambridge in the 1960s, there were about 8,000 men studying sciences there and only 800 women.
She married another PhD student working in a similar area, Tony Hunter, and they moved to La Jolla, San Diego to do postdoctoral studies, intending to return to England afterwards. However, while there, she formed a new relationship with a co-worker, John Kappler, and after the postdoc left to live with him in Rochester, New York, in 1973. They married and set up a joint lab, and have worked together closely since. Her parents moved from England to live near them and look after their grandchildren.
Marrack and Kappler moved to Denver to National Jewish Health and the University of Colorado in 1979. It was here that they and colleagues made a major breakthrough on T-cells in 1982, identifying the T-cell receptor (TCR), published in 1983. They fused 2 T-cells together, showing each had a single receptor to recognize antigens. The receptor is how the T-cells bind to antigens, enabling the T-cell to tackle the affected cells and fight off infection, cancer, or whatever disease they cause. A couple of other groups of researchers were homing in on the related issues and all 3 groups presented their work at conference in 1983.
In 1986, Marrack became one of the first Howard Hughes investigators, with generous funding. In 1987, building on the TCR work, she showed how the body recognizes T-cells that target its own tissues and destroys them in the thymus gland. Marrack describes her major areas of work and important findings over the years here.
(There’s an oral history interview with Marrack on YouTube.)
1986: Rachel Schneerson and colleague developed the first conjugate vaccine (for Haemophilus Influenza B meningitis) – using a carrier to boost effectiveness – leading to her Lasker Prize in 1996
Rachel Schneerson was born in 1932 in Warsaw, Poland. I couldn’t find any information about her family, or when she moved to Israel. She earned her medical degree from the Hebrew University in Jerusalem in 1958, and certified as a pediatrician in 1966. In 1969 she moved to the U.S. to the Albert Einstein College of Medicine in New York. There she met John Robbins, and they became research partners. They were both recruited to the National Institute of Child Health and Human Development (NICHD) in 1970, and they worked there until they both retired in 2012.
Schneerson and Robbins pioneered one of the most important breakthroughs in vaccine science – the first vaccine that wasn’t based on a whole virus. At the time, Haemophilus Influenza B (HiB) infection causing meningitis in early childhood, infected about 1 in 200 children in the U.S., with a high mortality rate. It was the leading cause of acquired intellectual disability in the U.S. They believed they could create a vaccine that caused a lower rate of adverse effects by using a single antigen to stimulate immunity – a polysaccharide, which is a sugar, though the scientific belief at the time was that only proteins could induce immunity.
Some polysaccharide-based HiB vaccines were licensed in 1985, but they weren’t effective enough to prevent HiB infection. So Schneerson and Robbins linked the polysaccharide to a protein carrier the child’s immune system would definitely respond to – a diphtheria toxoid. This new category was called the conjugate vaccine, and it worked.
Another pair of researchers were working on the same idea at the same time, although Schneerson and Robbins’ vaccine was the first effective vaccine. All 4 researchers were awarded the Lasker Prize. Schneerson and Robbins wrote an article about the search for effective HiB vaccine in 1987. They went on to work on a range of vaccines, including pertussis, typhoid, and anthrax.
1995: Kathrin Janssen and colleagues published the preclinical results for the first HPV vaccine
Kathrin Jansen was born in Erfurt, in then-East Germany, in 1958. Her interest in drug development was spurred by frequent bouts of illness as a child. “You’re a small person and you have this violent cough and you feel sick as a dog,” she said, “And then you get this drug. And it makes you feel better.” Her father was a chemical engineer in a large chemical company. The family fled to West Germany just before the Berlin Wall went up, drugged with sleeping tablets so she wouldn’t spill any beans to border guards.
Jansen studied biology at the University of Marburg in Germany, gaining her PhD in 1984. She had thought she had discovered a new chemical pathway, but her final experiment proved it to be an old one that had evolved. Jansen then did a postdoctoral fellowship at Cornell University, and her career has been in the pharmaceutical industry.
First she moved to Geneva to work in the Glaxo Institute there, then to the U.S. and Merck in 1992. Merck had bought the license to produce a vaccine based on part of the virus’ protein – it had been invented by Ian Frazer and Jian Zhou at the University of Queensland. It was intended to be produced using insect cells, but she and a colleague believed basing it on yeast would be better from a vaccine production viewpoint. She wrote about her life and the path to vaccine for cervical cancer here. Jansen and colleagues published the preclinical results for the HPV vaccine in 1995. The clinical trial results showing it was effective arrived in 2002 – she said she danced down the hallway with a colleague when the results came in. The vaccine, Gardasil, was approved in 2006.
Meanwhile, Jansen had left Merck in 2004 to become chief scientific officer at Vaxgen, and then to Wyeth in 2006 to lead vaccine development. There she led the development of a pneumoccocal vaccine. In 2010 she became an adjunct professor at the University of Pennsylvania. In 2009, Jansen moved to Pfizer, as Vice President and Head of Vaccine R&D.
Jansen forged the strong connection with the German company, BioNTech (BNT), that developed the BNT-Pfizer Covid vaccine, and as Matthew Herper writes, Pfizer was counting on her to give them the edge in the vaccine race. She certainly did, organizing that tour de force of a clinical trial that got them across the line before the end of 2020, and leading “a 650-person team night and day on Zoom meetings from her Manhattan apartment”.
Meanwhile, Katalin Karikó, “spent the 1990s collecting rejections” in the then-scientific backwater of mRNA technology. Chen Wei earned her PhD from China’s Academy of Military Medical Sciences. Sarah Gilbert joined the University of Oxford. Kizzmekia Corbett was still in high school! They and other women had pivotal and leading roles in developing Covid vaccines and been celebrated for it – with a spectacular roster of women scientists leading the clinical trials, too.
Disclosures: I wrote the Wikipedia page on Eva Klein in 2015 after seeing her name on Wikipedia’s timeline of immunology that’s the main source used for her here. Some of the section on Kathrin Jansen comes from a previous post I wrote on women leading clinical trials for Covid vaccines.