In study of hepatitis E vaccine, scientists pave new path for evaluating antibody responses
Under-the-hood study of a vaccine already approved in China offers a promising template for analyzing vaccine performance.
August 07, 2020
LA JOLLA, CA—A team including scientists at Scripps Research has published a comprehensive evaluation of the antibody responses induced by a viral vaccine—a type of evaluation that is made possible by modern sequencing technology and may become a standard feature of future vaccine development.
The scientists, who report their findings in Nature Communications, used advanced sequencing and cell-sorting technology to analyze the antibody responses to a hepatitis E vaccine in four volunteers. The vaccine, Hecolin, is produced in China and approved there for clinical use, but is also undergoing clinical trials aimed at obtaining approval in the United States.
Hepatitis E is a liver-infecting virus mainly spread by the fecal-oral route in unsanitary conditions and by improperly screened blood transfusions. It can cause severe or fatal disease in pregnant women or immunocompromised people, and is estimated to sicken tens of millions of people globally every year.
The study revealed that the inoculated volunteers varied significantly in the antibodies they produced in response to the vaccine. They also determined that the full course of vaccination, involving three injections over six months, is likely necessary to provide solid protection against the Hepatitis E virus for most people.
“Unlike traditional vaccine clinical trials, this study has provided a clear and comprehensive picture of a vaccine’s antibody-response landscape,” says Jiang Zhu, PhD, an associate professor in the Department of Integrative Structural and Computational Biology at Scripps Research, and one of the senior authors of the study. “In principle, this type of study could be done to evaluate a potential vaccine’s effectiveness early in development, before larger and more expensive studies are undertaken.”
The study was a collaboration involving Zhu’s lab and two labs at Xiamen University in China, and included the developers of the Hecolin vaccine.
At present, vaccines—including prospective COVID-19 vaccines—are tested in a series of increasingly larger clinical trials to determine side effects, the doses that work best, and ultimately their effectiveness at preventing infection. Analyses of vaccine recipients’ antibody responses are generally limited to broad measures of antibody levels in blood samples, as well as these antibodies’ grouped potency at neutralizing the virus or other pathogen.
However, advanced cell-sorting and gene-sequencing technologies now allow a more in-depth approach to the study of antibody repertoires and responses—an approach that Zhu has helped pioneer in recent years, particularly in the context of HIV research.
In the new study, the researchers used this approach to examine in detail, based on blood samples taken at seven time-points over a year, the antibody responses to the Hecolin vaccine in four healthy young volunteers—two women and two men.
In each sample, the team isolated individual antibody-making B cells, and sequenced the cells’ antibody genes. The researchers focused on B cells that make antibodies against the hepatitis E virus, and tested each antibody for its ability to bind and neutralize the virus’s infectivity.
In this way, the researchers were able to trace the appearance and proliferation of key virus-neutralizing B cells from the time of the first dose until more than six months after the third and final dose.
One finding was that a single dose regimen would have had doubtful effectiveness—most of the B cells producing antibodies against the viral protein in the vaccine appeared only after the second dose, which was given at the one-month time-point. The researchers also observed a continued strong increase in the levels of virus-neutralizing B cells after the last dose, again suggesting that a three-dose regimen, spaced over six months, may be desirable for vaccines such as Hecolin that use viral proteins—rather than, say, live but weakened virus—to stimulate the immune system.
“Some of the best antibodies were generated only after the third dose,” Zhu says.
The analysis showed that two of the four participants already had hepatitis E-reactive B cells in their blood samples even before receiving the vaccine, suggesting that virus-specific antibodies—whose numbers would of course expand after vaccination—may be frequently found in the ordinary human antibody repertoire.
The results moreover indicated a diversity in the participants’ antibody responses, such that each relied on a different mix of hepatitis E-neutralizing antibodies of varying potency.
“This underlying diversity in the response is something that traditional serum tests in vaccine studies could miss completely,” Zhu says.
The findings on the whole suggested that each vaccinated participant ended up, after three doses, with ample levels of potent virus-neutralizing antibodies, which is consistent with the strong performance of the vaccine in clinical trials so far. The analysis also indicated that these vaccine-induced antibodies had a significant ability to neutralize multiple strains, or genotypes, of the virus.
The researchers regard the study as valuable not only in the context of testing the Hecolin vaccine, but as an example or template for future studies of this kind that “go under the hood” to quantify vaccine antibody responses.
In addition to Zhu, the co-senior authors of the study, “Quantitative evaluation of protective antibody response induced by hepatitis E vaccine in humans,” were Zi-Zheng Zheng and Ning-Shao Xia of Xiamen University.
Funding was provided by the National Natural Science Foundation of China (81871247, 31730029, and 81701576), the Major Infectious Disease Project of China (2018ZX10101001-002), the Scientific Research Foundation of State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics (2018ZY001), and the U.S. National Institutes of Health (P01 AI124337, R01 AI129698 and R01 AI140844).
For more information, contact press@scripps.edu