DUBLIN – Three different vaccine technologies are being deployed in the desperate global effort to combat the SARS-CoV-2 virus, but Rino Rappuoli, chief scientist at the GSK Vaccines arm of Glaxosmithkline plc, said he sees traditional protein-based adjuvanted subunit vaccines, the trusted workhorse of infectious disease prevention, as offering the best bet for delivering a safe and effective vaccine at scale, within the tight timescales necessitated by the present crisis.

Rappuoli, who stressed he was speaking in a personal capacity, offered his perspectives on vaccine development during a webinar on the “Epidemiology and Economics of Coronavirus,” organized by the Sustainable Development Solutions Network, a UN initiative led by economist Jeffrey Sachs.

Rappuoli, who is among the world’s most influential vaccine scientists, actually helped to pioneer synthetic-genomic approaches for rapid vaccine development seven years ago. His group – then at Novartis Vaccines and Diagnostics – was part of a collaboration with Craig Venter’s Synthetic Genomics, which developed a rapid mRNA vaccine in response to the potentially pandemic H7N9 influenza strain that emerged in China in 2013. A day after the sequence data became publicly available, the group got to work. “By day seven we had an RNA vaccine ready to go into mice,” he said. “At that time, this was a kind of pioneering thing,” he said. Now, virtually any academic lab in the world can do it. “You can make vaccines based on the information you get on the internet.”

Vaccines based on that approach have, not surprisingly, been fastest out of the block, therefore. Cambridge, Mass.-based Moderna Inc. completed its discovery work by Feb. 7 on an mRNA-based vaccine, mRNA-1273, which encodes the SARS-CoV-2 spike protein, and it administered the first dose on March 16. Mainz, Germany-based Biontech SE and Tübingen and Germany-based Curevac AG are also pursuing mRNA-based vaccines, among several other companies. “It’s fast, but it’s not yet proven,” Rappuoli said. And even if an mRNA-based vaccine proves effective, manufacturing capacity will be a problem, he added.

But synthetic genes encoding a viral antigen can also be produced and spliced into a viral vector within a matter of days. The SARS-CoV-2 spike protein has already been inserted into most of the standard vectors, such as adenovirus, chimpanzee adenovirus, poxvirus (modified Vaccinia ankara), cytomegalovirus and vesicular stomatitis virus. Johnson & Johnson Co., of New Brunswick, N.J., began working on adenovirus-based vaccines, using its Advac vector technology, in late January, and has now selected a lead program, which it aims to move into the clinic in September, with the hope of getting initial safety and efficacy data before year-end.

The general approach “is a little more mature than RNA,” Rappuoli said. “It’s not yet fully proven how effective this will be.” It has so far yielded just one licensed vaccine, Erbevo (rVSVDG-ZEBOV-GP live), the vaccine against Ebola Zaire virus infection developed by Merck & Co. Inc., of Kenilworth, N.J., which gained FDA approval in December.

Protein-based vaccines take a little longer to make because of the need to transform cells lines with the antigen of interest. With a synthetic gene, that takes two to three weeks, Rappuoli said. But the approach is tried and trusted. “We are very comfortable that these vaccines will work,” he said. “My feeling is that if we are going to need hundreds of millions of doses to cover the global need, we will need this type of vaccine,” he said.

Protein-based vaccines need adjuvants, to boost the immune response against the antigen, to improve the breadth of the immune response should antigenic drift occur, and to enable dose sparing when supplies are limited. Existing adjuvants will be needed, given the length of time required to develop novel adjuvants. In that context, London-based GSK has entered a research collaboration with Sichuan Clover Biopharmaceuticals, Inc., of Chengdu, China, to evaluate in preclinical studies GSK’s pandemic adjuvant system with Clover’s candidate vaccine, COVID-19 S trimer.

But the discovery phase of vaccine development represents just 10% of the work. Formal preclinical and clinical development and manufacturing take a lot longer – and require a lot more cash. “Making a vaccine that works in the lab is pretty easy; scaling up and making a vaccine and getting to licensure so it is available for people is a much, much bigger investment,” Rappuoli said. One important safety issue to address in the development of COVID-19 vaccines is the risk of antibody-dependent enhancement, in which a vaccine can actually increase the severity of the disease. That has been a problem in the development of vaccines against dengue virus. “We don’t know if that’s going to happen for COVID, but some animal models have suggested it,” he said.

It normally takes up to 15 years to develop a new vaccine. Merck got the job done with Ebola in five. But the current – wildly optimistic – ambition is to deliver a vaccine within 18 months. “Now we have a lot of new technologies, which we can use to shorten development timelines,” Rappuoli said. “We need to embrace the new technologies, be courageous, work very closely with the regulatory agencies and move very fast.”

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