Virus World

The investigational vaccine known as mRNA-1273 was 94.1% efficacious in preventing symptomatic coronavirus disease 2019 (COVID-19), according to preliminary results from a Phase 3 clinical trial reported in the New England Journal of Medicine. The vaccine also demonstrated efficacy in preventing severe COVID-19. Investigators identified no safety concerns and no evidence of vaccine-associated enhanced respiratory disease (VAERD). The vaccine was co-developed by Moderna, Inc., a biotechnology company based in Cambridge, Massachusetts, and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health. Moderna(link is external) and NIAID previously shared initial results from the COVE trial. On Dec. 18, 2020, the FDA issued an Emergency Use Authorization(link is external) allowing Moderna to make the vaccine available for the prevention of COVID-19 in adults in the United States. The trial was led by principal investigators Lindsey R. Baden, M.D. of Brigham and Women’s Hospital in Boston, Hana M. El-Sahly, M.D. of Baylor College of Medicine in Houston, and Brandon Essink, M.D., of Meridian Clinical Research. The trial was implemented under the U.S. government’s Operation Warp Speed program and supported by NIAID and the Biomedical Advanced Research and Development Authority (BARDA) of the U.S. Department of Health and Human Services’ Office of the Assistant Secretary for Preparedness and Response.

The trial began on July 27, 2020, and enrolled 30,420 adult volunteers at clinical research sites across the United States. Volunteers were randomly assigned 1:1 to receive either two 100 microgram (mcg) doses of the investigational vaccine or two shots of saline placebo 28 days apart. The average age of volunteers is 51 years. Approximately 47% are female, 25% are 65 years or older and 17% are under the age of 65 with medical conditions placing them at higher risk for severe COVID-19. Approximately 79% of participants are white, 10% are Black or African American, 5% are Asian, 0.8% are American Indian or Alaska Native, 0.2% are Native Hawaiian or Other Pacific Islander, 2% are multiracial, and 21% (of any race) are Hispanic or Latino. From the start of the trial through Nov. 25, 2020, investigators recorded 196 cases of symptomatic COVID-19 occurring among participants at least 14 days after they received their second shot. One hundred and eighty-five cases (30 of which were classified as severe COVID-19) occurred in the placebo group and 11 cases (0 of which were classified as severe COVID-19) occurred in the group receiving mRNA-1273. The incidence of symptomatic COVID-19 was 94.1% lower in those participants who received mRNA-1273 as compared to those receiving placebo.  Investigators observed 236 cases of symptomatic COVID-19 among participants at least 14 days after they received their first shot, with 225 cases in the placebo group and 11 cases in the group receiving mRNA-1273. The vaccine efficacy was 95.2% for this secondary analysis. There were no concerning safety issues with vaccination, according to the authors. Local reactions to the vaccine were generally mild. About 50% of participants receiving mRNA-1273 experienced moderate-to-severe side effects — such as fatigue, muscle aches, joint pain and headache — after the second dose, which resolved in most volunteers within two days.

Investigators also observed no evidence of VAERD among those who received mRNA-1273. This rare complication was seen in individuals vaccinated with a whole-inactivated respiratory syncytial virus (RSV) vaccine in the 1960s, before there was a capacity to define protein structures and measure immune responses with precision. VAERD can occur when a vaccine induces an immune response that is not strong enough to protect against infection. Although mRNA-1273 is highly efficacious in preventing symptomatic COVID-19, there is not yet enough available data to draw conclusions as to whether the vaccine can impact SARS-CoV-2 transmission. Preliminary trial data suggests there may be some degree of prevention of asymptomatic infection after a single dose. Additional analyses are underway of the incidence of asymptomatic infection and viral shedding post-infection to understand the vaccine’s impact on infectiousness. The authors concluded by discussing the unprecedented efficiency of the candidate vaccine’s development, noting, “this process demonstrates what is possible in the context of motivated collaboration among key sectors of society, including academia, government, industry, regulators and the larger community.”

Findings Published in NEJM (Dec. 30, 2020):

https://doi.org/10.1056/NEJMoa2035389

A five-year-old girl with Mucopolysaccharidosis Type IIIA (MPS IIIA) has died in the Phase II/III AAVance clinical trial (NCT03612869), designed to evaluate the efficacy of Lysogene’s gene therapy candidate LYS-SAF302 in improving or stabilizing the neurodevelopmental state of MPS IIIA patients, the company has acknowledged. In a statement, Lysogene said the immediate cause of death was unknown, that additional information was being collected, and that no evidence had surfaced linking the death to the administration of LYS-SAF302. “Lysogene is profoundly saddened by the passing of this child and extends its deepest sympathies to the family. The company remains committed to the LYS-SAF302 development program and the Sanfilippo patient community,” the company said October 15 in a statement.  The company added that per study protocol, it was “diligently” following the 18 other patients who have been treated in the AAVance trial, conducted at eight clinical sites. The girl died at home several months after receiving the therapy, which Lysogene told French news agency AFP consisted of a single injection administered at one of the four U.S. clinical sites. Lysogene shares have tumbled 21% since news of the death became public, falling to €1.99 ($2.36) at the close of trading Friday, from €2.53 ($3.00) the day before the announcement.

Earlier clinical hold

The FDA on June 5 issued a clinical hold for the trial following observations in some patients of localized findings on MRI images at the intracerebral injection sites, suggesting a potential connection to delivery, Lysogene disclosed. But the company added that “no clinical symptoms have been observed that could be directly attributed to the observed MRI findings.” LYS-SAF302 is an adeno-associated virus (AAV)-mediated gene therapy for MPS IIIA, also called Sanfilippo syndrome type A, that is designed to work by replacing the faulty SGSH (N-sulfoglucosamine sulfohydrolase) gene with a healthy copy of the gene. SGSH is involved in producing an enzyme necessary for the breakdown and disposal of long chain sugar molecules. MPS III is caused by mutations in the SGSH gene, which encodes Heparan-N-sulfamidase for heparan sulfate (HS) recycling in cells. LAF-SAF302 is intended to deliver a functional copy of the SGSH gene and allow the brain to secrete the missing enzyme. LYS-SAF302 employs the AAVrh10 virus, chosen for its ability to target the CNS. The trial is designed to show improved or stabilized neurodevelopmental status of MPS IIIA patients.

Trial to enroll up to 20 patients

LAF-SAF302 is intended to deliver a functional copy of the SGSH gene and allow the brain to secrete the missing enzyme. The goal of the trial is to show improved or stabilized neurodevelopmental status of MPS IIIA patients. The trial was designed to enroll up to 20 patients at eight sites in the United States and Europe. Lysogene granted Sarepta Therapeutics exclusive commercial rights to LYS-SAF302 in the United States and other markets outside Europe in 2018. Sarepta agreed to pay Lysogene $15 million at the close of their licensing agreement, up to approximately $125 million in development, regulatory, and commercial milestone payments, plus sales-based royalties. Sarepta also made an equity investment in Lysogene of $2.5 million under the licensing agreement, which included Lysogene granting to Sarepta option rights to an additional CNS-targeted gene therapy candidate. Lysogene’s patient death occurred months after the deaths of three patients in the Phase I/II ASPIRO trial (NCT03199469), in which Audentes Therapeutics, an Astellas company, was evaluating its gene therapy candidate AT132 in patients with X-linked Myotubular Myopathy (XLMTM). All three were treated with the trial’s high dose of 3×1014 GC/kg, and began to demonstrate signs of liver dysfunction within 3 to 4 weeks after dosing. The AT132 program remained on clinical hold as of October 16.

AstraZeneca and the University of Oxford's coronavirus vaccine's high efficacy may have been in part due to a dosing error. In the press release on the vaccine's efficacy released on Monday, the vaccine candidate had a higher efficacy - up to 90% - in the group that received a half dose and then a full dose.  But the candidate vaccine was just 62% effective in the group that received two full doses. Mene Pangalos, head of biopharmaceuticals research and development at AstraZeneca, admitted to Reuters on Monday that some participants received a half dose and then a full dose due to a dosing error. Pangalos called it a "useful mistake" in a later interview with the New York Times, published on Wednesday. Oxford University said in a statement on Wednesday that some of the vials in the trial did not have the right concentration of vaccine. The university said the problem was discussed with regulators and they decided to complete the late-stage trial in two groups, according to the AP. 

Experts say the small number of people in the low dose group - some 2,741 - make it difficult to know if the effectiveness is a statistical quirk.  Also, none of the people in the low dose group were over 55 years old and younger people tend to have a stronger immune response than those who are older. A spokesperson for the University of Oxford told Euronews that "as a result of a difference in the manufacturing process" the phase I trial method was "shown to over-estimate the dose on the new batches of vaccine resulting in a half dose of the vaccine being administered as the first dose". After discussing with the regulator, the two different concentrations were tested in phase III trials.vDavid Salisbury, an associate fellow of the global health program at Chatham House said another area of confusion is that the press release pooled results from the two groups to reach an average of 70% efficacy. “You’ve taken two studies for which different doses were used and come up with a composite that doesn’t represent either of the doses,″ Salisbury told the AP. “I think many people are having trouble with that.″ 

Researchers say a smaller first dose could be more effective because you need just the right amount to get a good immune response. Some have criticised AstraZeneca and Oxford for a lack of transparency in the results release.  "Astrazeneca/Oxford get a poor grade for transparency and rigor when it comes to the vaccine trial results they have reported. This is not like Pfizer or Moderna where we had the protocols in advance and a pre-specified primary analysis was reported," Natalie Dean, an assistant professor of biostatistics at the University of Florida. "If they seek to get the half-dose approved, they should wait until they have a compelling result. Otherwise, we can land in 'evidence limbo.'"  More detailed results from the trials are expected to be provided to regulators who will decide whether to authorise the vaccine. Moncef Slaoui, who leads the US coronavirus vaccine program, said in a call with reporters that US officials are trying to determine what immune response the vaccine produced.  They may decide to modify the AstraZeneca study in the US to include a half dose: “But we want it to be based on data and science,” he said. Euronews has reached out to AstraZeneca for comment.