It was October 1996, and the call from my NIH program officer arrived around 7 AM. Dr. Pamela McInnes liked to keep projects on track. She wasted no time in letting me know what had to be done next if our newly prepared GBS conjugate vaccine was to be evaluated in pregnant women. The vaccine would have to pass a developmental toxicity test, she said. At that time, I had a general understanding of what she meant, but I was about to learn a great deal about a different aspect of vaccine development. In the process, I also realized that our undertaking would be a critical test for our new vaccine. Dr. McInnes needed to ensure that this study would be performed as well as it could be. Towards that end, she consulted with Dr. Michael Wessels and Dr. Dennis Kasper at Harvard as well as experts at the FDA on the best way to design a developmental toxicity study for a vaccine that would be administered to women during pregnancy in order to protect their babies at birth.
In order for any experimental vaccine to be administered to healthy pregnant women it must be manufactured under current good manufacturing practices (cGMP), and it also must pass a development toxicity test. cGMP follows FDA-regulated design, monitoring and control of manufacturing practices, the high standards used by biopharmaceutical industry. A developmental toxicity study is undertaken to determine if a chemical or biologic poses a risk to a pregnant woman or to the developing fetus.
This undertaking was a new challenge for me. It was a rare opportunity to be a part of such an important effort – one that forced me to think differently.
Academic scientists undertake hypothesis-driven research – studies that attempt to reveal underlying mechanisms to a specific problem such as the interactions and pathways that lead certain cells to become cancerous, or in exploring environmental cues that make harmless bacteria become dangerous. Normally, overseeing the production of a cGMP lot of vaccine and designing a developmental toxicity study would not be the concerns of academic researchers because the intellectual fruits of getting the vaccine to this point would have been harvested. The downstream steps such as vialing, advanced clinical testing, marketing and distribution, were concerns of the biopharmaceutical industry where expertise resides. But, at that time industry had other priorities. By 1996 many GBS researchers at universities across the country, as well as those at the NIH, were intellectually well-vested in the development and testing of a GBS vaccine. Collectively we were determined to advance this effort as far as possible. The next step in the pathway to a safe and effective vaccine against neonatal GBS disease was clear: a developmental toxicity study.
Thanks to the talented scientists at Argus Laboratories who were experts in performing development toxicity studies, our role as academic researchers was simple. We had to design the study to answer two important questions: Is the vaccine itself a developmental toxicant and, are antibodies raised to the vaccine developmental toxicants?
For many reasons rabbits were the ideal choice for this important undertaking including the fact that early studies showed that they respond very well to GBS conjugate vaccines. As usual, work performed with animals adhered strictly to established federal guidelines. Rabbits received the GBS vaccine at 20- to 100-fold greater amounts on a weight basis than was anticipated for use in humans. If the vaccine, or antibody to the vaccine, led to a developmental issue, we would be sure to see it.
With the protocols reviewed and re-reviewed, the doses confirmed and re-confirmed, and study goals and parameters finalized, a development toxicity study with a GBS conjugate vaccine was, for the first time in history, underway. The long, nerve-wracking wait began. Finally, the precious serum samples from Argus Research Laboratories arrived and we measured the level of specific antibody as designed from the onset. We were not surprised to see that the rabbits made generous amounts of specific antibody to the GBS conjugate vaccine, but what about the development toxicity parameters?
It was November 20, 1997, over a year after that early morning phone call with Dr. McInnes, when we received the preliminary report from Argus Research Laboratories:
There were no clinical or necropsy observations that were considered related to the administration of the vaccine;
Administration of the vaccine did not affect maternal body weights, changes or absolute, or relative feed consumption throughout the study period;
C-sectioning and litter parameters were not affected by the vaccine;
No gross external, soft tissue or skeletal malformations or variations in the fetuses were considered effects of the vaccine;
All natural delivery and litter parameters were unaffected by the vaccine. Viable indices were comparable between (test and control) groups;
Live litter sizes over the lactation period, pup survival, sex ratio, and pup body weights were comparable among the four groups.
The team at Argus independently concluded that GBS type III polysaccharide-tetanus toxoid conjugate vaccine should not be identified as a developmental toxicant. Indeed, the final report, published in Human Vaccines, stated that the vaccine, as well as antibody raised to it, are not developmental toxicants.
The developmental toxicity study was just one of many key hurdles that needed to be cleared before the FDA would approve the all-important, first-of-its-kind maternal vaccine trial of a GBS conjugate vaccine. While the academic’s pursuit of a vaccine usually ends with discovery, there is value in keeping researchers engaged – sometimes there are hidden fruits to be discovered.
Click HERE to read Dr. Paoletti's firsthand account of vaccine history in the making in:
Dr. Paoletti’s research career focused on the development and testing of GBS conjugate vaccines. He is now a Research Associate at Harvard Medical School and a paid consultant for PATH’s GBS vaccine program.