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Australia's First MRNA Covid Vaccine Candidate Could Solve 'immune Imprinting' Problem — Here's What That Could Mean

Researchers developing Australia's first mRNA Covid vaccine say they may have solved the "immune imprinting" issue that has contributed to the declining effectiveness of boosters as the virus mutates.

Immune imprinting, also known as original antigenic sin, occurs when the body's original immune response to a virus — either from vaccination or infection — becomes less effective against new variants of the same virus.

The Australian-based vaccine candidate, being developed by the Monash Institute of Pharmaceutical Sciences (MIPS) in collaboration with the Doherty Institute, aims to tackle the problem by encoding the proteins on the surface of the receptor-binding domain — the tip of the virus 'spike'.

In a preclinical study, published in Molecular Therapy Methods and Clinical Development, the researchers tested their mRNA 'membrane-anchored receptor-binding domain' (mRNA RBD-TM) vaccine against ancestral Covid vaccines by comparing third-dose immune responses to Omicron variants in mice.

A pharmacist administers a COVID-19 vaccination booster shot to a customer. Getty Images

The study showed a 16.3-fold increase in antibodies for the mRNA RBD-TM vaccine compared with 1.3 for the ancestral vaccine, despite previous exposure to the SARS-CoV-2 virus, suggesting the potential to overcome immune imprinting.

"The concept of immune imprinting is not a new one — the same phenomenon occurs with influenza, and there is now mounting evidence of widespread imprinting attributed to exposure to ancestral Covid-19 strains," Professor Colin Pouton from MIPS said in a statement.

"To address this, we developed an alternative platform designed to target SARS-CoV-2 virus mutations in the tip of the 'spike', otherwise known as the receptor binding domain. We found that, when administered as a third-dose booster following two doses of ancestral vaccine … our vaccine was able to effectively induce new variant-specific antibodies, making it a promising next-generation candidate to protect against new and emerging Covid-19 strains."

Next-generation Covid vaccines are being trialled in Melbourne. Getty Images

Prof Pouton said next-generation Covid vaccines were needed to protect ageing and vulnerable populations from future mutant strains of the virus.

Lead author Dr Harry Al-Wassiti said the study could help pave the way for developing a new refined, homegrown vaccine to protect against Covid-19.

"Another advantage to the mRNA RBD-TM vaccine is that, because it's about a quarter of the size of its whole-spike equivalents, it could be effective at lower doses, therefore making it more tolerable," he said.

"Its smaller mRNA size also means it can be more stable at higher storage temperatures, a feature important for future mRNA vaccines."

Professor Damian Purcell from the Doherty Institute said, "Our 20 years of prior University of Melbourne research on prototype RNA vaccines and on protective antiviral immunity encouraged us to prioritise rigorous research and development of the Monash mRNA RBD-TM vaccine candidate.

mRNA Victoria aims to turn the state into the "leading hub in the Asia-Pacific for mRNA and RNA research, commercialisation, advanced manufacturing and workforce training". Getty Images

"We used our broad resources to demonstrate that safe and effective immune responses were generated in mice against new immune-evading variant virus isolates."

The MIPS Covid-19 mRNA vaccine has already completed a phase one clinical trial as a fourth-dose booster.

Prof Pouton said ideally the next step would be to test the mRNA RBD-TM candidate in clinical trials to further validate its effectiveness as a next generation Covid vaccine to address immune imprinting.

Monash University's Covid vaccine was the first mRNA vaccine candidate developed and manufactured for clinical trials in Australia, funded by the Victorian government through mRNA Victoria.

A pharmacist administers a COVID-19 vaccination booster shot to a customer at Exhibition Pharmacy on July 11, 2022 in Melbourne, Australia. Getty Images

Established in May 2021, mRNA Victoria aims to turn the state into the "leading hub in the Asia-Pacific for mRNA and RNA research, commercialisation, advanced manufacturing and workforce training".

Messenger RNA (mRNA), a type of single-stranded molecule involved in protein synthesis, has been researched for decades but was not widely used until the Covid vaccines.

The technology is now being applied to a range of other illnesses including infectious diseases, Alzheimer's and cancer.

mRNA Victoria has so far funded 57 research projects for a total of nearly $29 million, and has partnered with Moderna on the construction of an mRNA vaccine manufacturing facility in Clayton, capable of producing up to 100 million vaccine doses per year.

The Australian government currently recommends a booster dose every six months for everyone aged 75 and older, every 12 months for those aged over 65, and every 12 months for over 18s with severe immunocompromise.

Adults without severe immunocompromise and children aged five to 17 with severe immunocompromise are eligible for a booster every 12 months.

A total of 930,000 doses were administered in the six months to December 11.

The latest Health Department figures show 18.5 per cent of over-75s have had a booster in the last six months, 9.6 per cent of those aged 65 to 74, and just 1.8 per cent of over-18s.

Studies Describe Vaccine Efficacy Against Long COVID

Two new large studies, one based on outcomes among US children and teens and the other on adults in Japan, show COVID-19 vaccines are protective against long COVID. Both studies were conducted when the Omicron strain of the virus was dominant, with the first also assessing the Delta variant. 

In the first study, published in eClinicalMedicine, researchers measured the real-world efficacy of the Pfizer-BioNTech (BNT162b2) vaccine against long COVID in children and adolescents using data from 20 US health systems collected in as part of the RECOVER PCORnet electronic health record (EHR) Program.

Three cohorts were constructed: (1) adolescents 12 to 20 years old during the Delta phase (July 1 to November 30, 2021), (2) children 5 to 11 years and (3) adolescents 12 to 20 during the Omicron phase (January 1 to November 30, 2022). Outcomes were compared among those who received a first dose of the Pfizer vaccine to those with no receipt of COVID-19 vaccines.

In total, 112,590 adolescents (88,811 vaccinated) were included in the cohort for the analysis against the Delta variant, and 188,894 children (101,277 vaccinated), and 84,735 adolescents (37,724 vaccinated) were included for the analysis against the Omicron variant.

Preventing long COVID by averting infections 

For adolescents during the Delta period, the estimated effectiveness of the BNT162b2 vaccine against long COVID was 95.4% (95% confidence interval [CI], 90.9% to 97.7%). During Omicron, the estimated effectiveness against long COVID among children was 60.2% (95% CI, 40.3% to 73.5%), and it was 75.1% (95% CI, 50.4% to 87.5%) among adolescents.

The risk reduction in developing long COVID was largely linked to reducing the risk of COVID infection in the first place. 

The effects through protecting againt SARS-CoV-2 infections were estimated as 0.04 (95% CI, 0.03 to 0.05) among adolescents during Delta phase, and 0.31 (95% CI, 0.23 to 0.42) among children and 0.21 (95% CI, 0.16 to 0.27) among adolescents during the Omicron period.

The higher effectiveness of the BNT162b2 vaccine during the Delta phase, relative to the Omicron period, can be attributed both to its protection against Delta infections and to the fact that the primary benefit of the vaccine on long COVID stems from its capacity to prevent infection.

"The higher effectiveness of the BNT162b2 vaccine during the Delta phase, relative to the Omicron period, can be attributed both to its protection against Delta infections and to the fact that the primary benefit of the vaccine on long COVID stems from its capacity to prevent infections," the authors concluded. "With the genetic evolution of Omicron strains that generally are more highly transmissible with much lower severity of symptoms, infection rates are higher and vaccine effectiveness has been lower."

Three or more doses tied to less long COVID in women 

In the second study, a population-based analysis from Japan, researchers found the vaccine effectiveness of three or more doses of COVID vaccine against Omicron-related long COVID to be 30%, and against neurologic symptoms of long COVID it was 39%. 

The protection, however, was found only in women. The study was published yesterday in Clinical Microbiology and Infection. 

A total of 7,936 participants aged 20 to 69 years, who were infected from July 1 to August 31, 2022, were included in the study. Of those, 940 (11.8%) had at least one post-COVID, or long-COVID, symptom, according to a self-administered questionnaire. 

Participants who had three or more COVID-19 vaccine doses had a 30% lower probability of long-COVID symptoms, with the odds ratio (OR) of 0.70 (95% CI, 0.53 to 0.90), although there was no association with one or two doses.

Furthermore, the risk reduction was seen in women with three or more COVID vaccine doses but not in men. 

There was no significant association for respiratory symptoms, but those with three or more COVID vaccine doses reported fewer neurologic symptoms compared to unvaccinated participants (OR, 0.61; 95% CI, 0.45 to 0.83).

FDA Grants Fast-track Status To Combination MRNA Flu And COVID-19 Vaccine Candidates

The FDA has granted fast track designation to two combination vaccine candidates that aim to protect adults 50 and older from both influenza and COVID-19, according to a Dec. 16 AJMC report. 

These vaccine candidates combine the flu vaccine with the Novavax COVID-19 vaccine, offering a potential single shot to address both diseases. 

The designation was granted to expedite the development of vaccines that could help reduce the health burdens of flu and COVID-19, especially for groups that are at higher risk of severe outcomes such as prolonged hospital stays and long-term complications. 

The first combination candidate combines Fluzone High-Dose, a high-dose flu vaccine, with Novavax's COVID-19 vaccine. The second candidate uses Flublok, a recombinant flu vaccine paired with the same Novavax COVID-19 vaccine.

Both flu vaccines have been shown to be more effective than standard-dose flu vaccines in preventing infections and reducing hospitalizations in older adults. The Novavax COVID-19 vaccine has also demonstrated good safety and efficacy profiles in previous clinical trials, according to the release. 

Sanofi, which is developing the vaccines, has launched phase ½ clinical trials to evaluate the safety and immune responses to the combination shots. The trials aim to assess whether combining these vaccines can maintain their efficacy while simplifying vaccination schedules, potentially improving uptake among older adults. 

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