A third messenger RNA (mRNA) vaccine appears to have proven its worth against COVID-19. And even though it’s more than a year behind the Moderna and Pfizer BioNTech vaccines, now seen as gold standards, the new vaccine can come with significant benefits: easier storage along with lower costs, because its “self-reinforcing” design allows for less doser.
Arcturus Therapeutics of San Diego, which staged a placebo-controlled trial with its candidate in more than 17,000 participants in Vietnamannounced it yesterday in a press release that the vaccine had a 55% effect against symptomatic COVID-19 and gave a 95% effect against severe illness and death. “It’s a huge achievement that a self-amplifying RNA vaccine has been shown to be safe and effective for the first time,” said Deborah Fuller, a vaccinologist at the University of Washington School of Medicine who is an advisor to HDT Bio, which has its own self-amplifying COVID-19 mRNA vaccine in human studies.
Arcturus’ success may also help make mRNA vaccines more widely available. Its candidate incorporates a lyophilization process to convert the mRNA-filled solution to a powder that can be stored at room temperature and then rehydrated. This has much simpler cold chain requirements than the conventional liquid mRNA vaccines in use. And Vietnam’s Vinbiocare Biotechnology, which collaborated with Arcturus on the trial and has submitted the efficiency data to the country’s regulators for an emergency use permit, hopes to be able to manufacture the product there.
The Pfizer BioNTech and Moderna vaccines contain mRNA encoding the SARS-CoV-2 peak protein. When the vaccines are injected, they deliver the mRNA to cells, which make copies of spikes and then purify the foreign genetic material within a few days. Arcturus’ self-amplifying vaccine and others under development include alphavirus enzymes to repeatedly copy the genetic strand inside a cell and remain in the body for more than twice as long.
Some researchers have warned that self-amplifying vaccines cannot use an mRNA modification that is key to the Moderna and Pfizer BioNTech vaccines: replacing the natural RNA building block uridine with pseudouridine. Studies have shown that the prey leads to higher levels of the tip protein and lower production of immune chemicals called cytokines that can cause side effects. A conventional mRNA vaccine manufactured by CureVac failed in a efficacy trial last year, and some scientists suggested it may have been because it did not use pseudouridine. But Arcturus says the efficiency results disprove these concerns. “It’s a big deal for the field,” said Pad Chivukula, the company’s scientific director.
The trial, which began in August 2021, gave participants two doses, each containing 5 micrograms of the self-amplifying mRNA at 28-day intervals. The Pfizer-BioNTech and Moderna vaccines use 30 micrograms and 100 micrograms doses for the first two shots, respectively.
Like most COVID-19 vaccine manufacturers with new efficacy test results, Arcturus provided only a look at the results. The bottom line against symptomatic infection – 55% efficacy – is below the 90% to 95% seen in trials with the first two mRNA vaccines. However, these vaccines faced the original SARS-CoV-2 virus. The Arcturus candidate, based on a similar strain, was to protect against the Delta and Omicron variants that circulated in Vietnam during the experiment and which have evolved dramatically from the ancestral strain, reducing the effect of vaccine-triggered antibodies. Fuller says the current effectiveness of existing mRNA vaccines may be in the same ballpark. Of the 43 severe cases of COVID-19 detected by Arcturus during the trial, only two were in the vaccinated group and nine of the 10 people with COVID-19 who died received placebo.
“These are really exciting results,” said chemist Benjamin Pierce, who is helping run a Ugandan trial of a self-amplifying mRNA COVID-19 vaccine made by Imperial College London. “The low dose used here – six to 20 times lower than approved RNA vaccines – further indicates that self-amplifying RNA technology has such potential. I look forward to seeing more data from the trial.”
Fuller says a self-amplifying mRNA COVID-19 vaccine would ideally replace the two primary doses, giving it an even clearer advantage over its conventional relatives. A booster months later may still be warranted, as is now encouraged for current mRNA vaccines. But self-amplifying mRNAs can also lead to more lasting immune responses, Fuller suggests.
When the Arcturus trial began, less than 15% of the eligible Vietnamese population had received even a single shot of a COVID-19 vaccine. Now the figure is 80%, which raises the question of how the vaccine will work in the vast majority of people who have already been vaccinated or naturally exposed to SARS-CoV-2. Arcturus hopes to soon be able to launch a test of 2400 people to assess its value as a booster shot. This trial aims to show that the vaccine boosts antibody responses, as other studies have shown related to protection– although no new COVID-19 vaccine has yet received authorization from strict US or European regulators based on “immunobriding” data.
Pfizer-BioNTech and Moderna have received intense criticism for not quickly sharing their production capabilities and intellectual property with developing countries that have had relatively little access to their mRNA vaccines. Arcturus on the other hand in August 2021 agreed to a technology transfer agreement with Vinobiocare, which is building a factory in Hanoi to manufacture the vaccine.
But with much of the world vaccinated, the Arcturus vaccine may debut late, at least for primary vaccination. Chivukula is convinced that it will find a market in countries with far lower vaccination rates than Vietnam, and stresses that it will be at “a price point that everyone can afford.”