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FDA Seeks Sequencing Services for Evaluation of Viral Vaccine QC Technology

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By Monica Heger

In a step towards implementing sequencing in the vaccine production process, the US Food and Drug Administration is soliciting deep sequencing services for viral vaccines, In Sequence has learned.

The request follows the recent finding of a porcine circovirus in GlaxoSmithKline's rotavirus vaccine Rotarix (IS 4/6/2010). So far, Beckman Coulter Genomics and Macrogen have indicated interest in submitting proposals.

In its solicitation request, the FDA asks for sequencing services on both the Roche 454 and the Illumina Genome Analyzer, and says that the services will be used for the "regulatory evaluation of various methodologies/technologies used in vaccines/vaccine related products."

Agency officials could not be reached for further comment before In Sequence went to press.

The request follows a hearing last month of the FDA's Vaccine's and Related Biological Products Advisory Committee, in which members discussed sequencing's utility in insuring vaccine safety as part of a broader discussion regarding whether to discontinue the use of the vaccine (IS 5/11/2010).

The committee ultimately decided that the vaccine was safe. While it issued no formal recommendations regarding next-generation sequencing, it agreed that it was a powerful tool for uncovering contaminants in viral vaccines, and that regardless of the FDA's decision to implement the technology, sequencing would continue to be used to discover new contaminants, including both non-infectious agents such as the one found in the Rotarix vaccine, as well as infectious agents and novel viruses.

Eric Delwart, an investigator at the Blood Systems Research Institute in San Francisco who made the initial discovery of the porcine circovirus, told In Sequence he thought the FDA's move was a good one.

"In the long term, I think this will improve the safety and the reputation of vaccines," he said. "It will not change the development [of vaccines]. "It will mean that they are free of adventitious viruses."

So far, companies that have expressed interest in providing the sequencing for the FDA include Beckman Coulter Genomics and Macrogen, a sequencing service provider whose clients already include researchers at FDA, as well as other researchers in labs at the National Institutes of Health and the National Cancer Institute.

Beckman Coulter Genomics' clients include pharmaceutical companies and vaccine developers, and Beckman Coulter scientist Elena Jouravleva said that since the initial finding of the porcine circovirus, demand for vaccine sequencing services has shot up.

She said the requests have included the sequencing of the vaccine itself, to make sure that it was free from contamination, as well as the sequencing of the cell lines used to make the vaccine and the media used to grow the virus.

Jouravleva added that the company will submit a proposal for services on both the 454 and Illumina platforms. "As a company we are interested in working on this process," she said. Beckman Coulter offers sequencing on 454, Illumina, and SOLiD.

Jouravleva said that despite the fact that next-generation sequencing is not yet a validated Good Manufacturing Practices-compliant method for insuring vaccine quality, it could still be used in the vaccine production process. For instance, she said that sequencing could be done on the components used to make the vaccine, and if anything of concern was found, then a validated method, like qPCR, could be used to confirm the finding.

"So, from that perspective, this tool can be used today," she said. "You don't have to use it as a validated method." Instead, you can simply use it to "control your components up front, and if you do find something, you can pull it up with an already validated method."

Raising sequencing to the level of GMP compliance for vaccine production will be more complicated, Jouravleva said. In order to do that, researchers will have to demonstrate that sequencing can target and find specific agents of concern, and not just be a fishing expedition.

The sequencing experiments will also have to be reproducible and consistent. In the case of the Rotarix vaccine, there was a lot of variation in terms of the amount of virus that was detected when the experiment was repeated, Jouravleva said. For instance, Delwart's team tested additional vaccines, not just the Rotarix vaccine, and did not find contaminants in any of the other vaccines, including Merck's rotavirus vaccine RotaTeq. However, Merck later informed the FDA that when it tested RotaTeq itself, it found pieces of the porcine circovirus

"If you change instruments, or reagents, you still have to come up with the same answer," Jouravleva said. Additionally, you will "have to address not only the machine performance but also the library preparation, the extraction process, and the software."

Aside from the complexities of becoming GMP compliant, another issue is how incorporating sequencing into vaccine production could affect cost. Jouravleva said that initially, sequencing will add to the cost of vaccine development because companies don't currently perform that step.

In the long run, though, incorporating sequencing into the early stages of vaccine development could help reduce costs, because there won't be "surprises" in the finished product, she said. "You can change the existing line upfront, and you won't have to scrap the whole production line and start from scratch." GSK, for instance, will have to invest a lot of money and time into remanufacturing Rotarix, she said.

According to FDA's updated recommendations, GSK is working with the agency to re-derive its vaccine, while Merck "is in the early stages of its investigation, and has not yet determined next steps in this regard."

If sequencing ends up becoming a part of vaccine production and companies invest in their own machines, Delwart thinks that the technology could ultimately make more effective vaccines.

One of the biggest problems with vaccine development is the large amount of diversity within a virus, he said. "The strains of viruses [that you are protecting against] should reflect the strains of viruses on the street." He thinks sequencing could be used to help characterize the diversity within one target virus, so that the vaccine developed would protect against all forms.

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