CHICAGO, July 20 (Reuters) - Scientists are working on a benchmark for COVID-19 vaccine efficacy that would allow drugmakers to conduct smaller, speedier human trials to get them to market and address a huge global vaccine shortage. Researchers are trying to determine just what level of COVID-19 antibodies a vaccine must produce to provide protection against the illness. Regulators already use such benchmarks - known as correlates of protection - to evaluate flu vaccines without requiring large, lengthy clinical trials. "You could use it to predict efficacy from a vaccine, which will be more important as we are less able to conduct placebo-controlled trials," said Stanley Plotkin, inventor of the Rubella vaccine and an expert on correlates of protection. "The information is flowing in," he said. "By the end of this year, I think there will be enough data to convince everyone."An established benchmark for COVID-19 would allow drugmakers to conduct vaccine trials in just a few thousand people, about one-tenth the size of the studies conducted to gain authorization for currently widely-used coronavirus shots, researchers and drugmakers told Reuters. Those studies, involving tens of thousands of volunteers, compared the rate of COVID-19 infections in people who received the shot with the rate in participants who got a placebo. Such randomized, controlled trials may no longer be considered ethical in some countries, as researchers cannot give a dummy shot to people where an effective vaccine is widely available. In addition, many of the new shots are being developed by small companies that may not be able to conduct very large trials without government funding or a partner with deep pockets. With an established correlate, drugmakers could test blood samples from a smaller number of trial participants who receive an experimental vaccine to see whether they produced that benchmark level of protective antibodies. Such a benchmark is “urgently needed” to help overcome challenges faced by vaccine developers and boost availability of shots, Dr. Florian Krammer, a virologist at the Icahn School of Medicine at Mount Sinai in New York wrote this month in the journal Nature. Researchers at Oxford University late last month proposed a potential correlate of protection based on antibodies found in people who had received the AstraZeneca (AZN.L) vaccine. The work awaits peer reviewed by other scientists. Results from a U.S.-backed study of Moderna’s (MRNA.O) vaccine are expected to be published in a medical journal later this summer. "We"re writing the paper right now," said Dr. Peter Gilbert, a biostatistician from the Fred Hutchinson Cancer Research Center. Some vaccine experts question whether antibody levels will be a strong enough indicator of protection. Other components of the immune system, such as T-cells and B-cells, are thought to provide important defenses against COVID-19, but are more difficult to measure. That has been the contention of some top vaccine experts at Pfizer (PFE.N), maker along with BioNTech of one of the most effective COVID-19 vaccines, produced in the largest quantities globally. It is also possible that each different type of coronavirus vaccine will require its own correlate, some experts said. Drugmakers working on a new type of vaccine likely would not be able to rely on the correlates based on Moderna’s messenger RNA shot, they say. BRIDGING THE GAP Meanwhile, vaccine developers are trying to devise acceptable substitutes to huge, placebo-controlled trials. Some aim to show their shot provokes antibody responses at least as good as those seen with currently authorized shots. European and UK health regulators are working with companies to set standards for these so-called “immunobridging” studies. The U.S. Food and Drug Administration declined to say whether it would accept such trials for next-generation vaccines. “It doesn"t have to be an established correlate of protection, but we have to ... arrive at the right pre-specified criteria, because we cannot risk that a second-generation vaccine ... is of low or modest vaccine efficacy," FDA vaccine official Dr. Marion Gruber told fellow regulators at a World Health Organization Meeting in May. "That would undermine confidence in the vaccine enterprise." Italy"s ReiThera Srl is developing a vaccine using technology similar to AstraZeneca"s and will try to demonstrate that its shot is at least as effective. The company has an agreement in principle on trial design with European and British regulators, ReiThera"s senior director Stefano Colloca told Reuters. Massive clinical trials are "no longer ethical and feasible in most countries worldwide," he said. French biotech Valneva (VLS.PA) and Taiwan"s Medigen Vaccine Biologics Corp (6547.TWO) plan to test their vaccines against the AstraZeneca shot, even though both use a different technology. Valneva"s trial design was approved by UK regulators. Medigen has a green light from Taiwan. Sanofi (SASY.PA), with partner GlaxoSmithKline (GSK.L), and Canada’s Medicago are still opting for placebo-controlled trials involving thousands of participants, including in countries with high infection rates and fewer authorized vaccines available. NEED FOR BOOSTERS? The hunt for a correlate is underway from the UK to the United States and Australia. Scientists are comparing antibody levels in vaccinated people who became infected with COVID-19 to those who did not, to find a threshold of protection that made the difference. Oxford University researchers said work is needed to address correlates for emerging virus variants, such as the highly transmissible Delta that has quickly become dominant globally. read more Their proposed antibody model is based on trial volunteers who had mainly contracted the earlier Alpha variant, first identified in the UK. U.S. government-backed scientists are studying infections in people who received the Moderna vaccine. Moderna spokesman Ray Jordan said the company is also working on the analysis and will publish updates when available. The correlate benchmark might also indicate when and whether people need vaccine boosters. Pfizer has sought authorization for a third booster dose of its vaccine, citing evidence of waning neutralizing antibody levels. But the company has pushed back against the idea that those same antibodies could be used to predict vaccine efficacy. "No formal timeline is in place to have correlates of protection established," a Pfizer spokesperson said. "We will continue to work with the scientific community to better understand what immune responses, whether neutralizing antibodies or otherwise, might contribute to protection.”