A vaccine to prevent cervical cancer: academic and industrial collaboration and a Lasker award

I joined the Department of Virus and Cell Biology at Merck Research Laboratories in 1982, when Dr Maurice Hilleman was head of the Department, and Dr Roy Vagelos was President of Research. At the time, there were lingering concerns about theoretical safety issues of Merck’s first hepatitis B vaccine, called ‘Heptavax’, produced by purifying the native coat protein from the blood of virusinfected patients. In the first few months of my tenure at Merck, I became aware of the effort in the Virus and Cell Biology Department to produce a vaccine against hepatitis B from the recombinant viral coat protein to alleviate these concerns. Merck had licensed an expression system from Chiron, a biotechnology company, that had developed a protocol for expressing the gene encoding this 25 kD molecular weight protein in yeast, and Merck was attempting to increase the expression level, purify the protein and formulate it into a vaccine. Unexpectedly, when the protein was purified from the yeast, it was poorly immunogenic, making it unsuitable for a vaccine. We attempted multiple purification methods, and, ultimately, the research team and I deduced and proved that, by using potassium thiocyanate, we could convert the monomer to a particle that resembled the particle of the native virus. Building on this discovery, Merck went on to produce the first vaccine made by recombinant DNA methods, and ‘Recombivax HB’ was approved in the United States by the FDA in 1986. A few years passed, and in 1991, Jian Zhou and Ian Frazer, two virologists at the University of Queensland in Australia (Figure 1), stunned the audience at an international meeting on papillomaviruses (PVs) in Seattle. They presented data showing that they could produce, in mammalian cells using recombinant DNA methods, just the coat proteins (L1 and L2) of human papillomavirus 16, and the proteins assembled themselves into a virus-like particle, without the DNA of the virus. They called this structure a virus-like particle (‘VLP’). The audience was both stunned and sceptical of the work, but no less than Harald Zur Hausen, the Nobel Laureate who had discovered the role of HPV in certain human cancers, labelled the discovery as a breakthrough and a step towards a vaccine against cancer-causing HPV genotypes. Many scientists who subsequently entered the vaccine field were at the meeting, including Drs Denise Galloway, Ricjard Schelgel, and Schiller and Lowy. It is noteworthy that the work begun in the National Cancer Institute was not begun until September 1991 as shown in the materials examined during the patent discovery process. Shortly after this public meeting, a small group of scientists came to see me to ask for resources to begin a project to make a vaccine against HPV. They pointed out Merck’s history of using the yeast expression system and purification technology in the hepatitis B vaccine project and argued that they could now do the same with HPV, after obtaining any needed licences to patents from the Australian group. I had mixed thoughts about this proposal. On the one hand, I