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Moderna Vaccine

Moderna says Covid-19 vaccine protection wanes, makes case for booster


Story by asiaone.com

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Published on September 21, 2021 11:10 AM
 
 
Moderna said there was a trend toward a lower rate of severe cases among the more recently vaccinated, although the finding was not statistically significant. Moderna also highlighted a study published last week by the US Centres for Disease Control and Prevention looking at data from more than 32,000 visits to urgent care centers, emergency rooms and hospitals in nine states or major cities.
 
CHICAGO - New data from Moderna's large Covid-19 vaccine trial shows that the protection it offers declines over time, supporting the case for booster doses, the company said in a news release on Wednesday (Sept 15).

Several recent studies have suggested that its vaccine may have an edge over a similar shot from Pfizer and German partner BioNTech in terms of maintaining efficacy over time.

Experts said the difference is likely due to Moderna's higher dose of messenger RNA (mRNA) and the slightly longer interval between the first and second shots.

Both vaccines proved to be exceedingly effective at preventing illness in their large Phase III studies.

The analysis released on Wednesday, however, showed a chink in the Moderna shot's armor over time, with higher rates of infection among people vaccinated roughly 13 months ago compared with those vaccinated roughly eight months ago. The study has yet to undergo peer review.

Moderna on Sept 1 submitted its application to...

Moderna COVID-19 vaccine

The Moderna COVID-19 vaccine , codenamed mRNA-1273 and sold under the brand name Spikevax, is a COVID-19 vaccine developed by American company Moderna, the United States National Institute of Allergy and Infectious Diseases and the Biomedical Advanced Research and Development Authority .

It is authorized for use in people aged twelve years and older in some jurisdictions and for people eighteen years and older in other jurisdictions to provide protection against COVID-19 which is caused by infection by the SARS-CoV-2 virus. It is designed to be administered as two or three 0.5 mL doses given by intramuscular injection at an interval of at least 28 days apart.

It is an RNA vaccine composed of nucleoside-modified mRNA encoding a spike protein of SARS-CoV-2, which is encapsulated in lipid nanoparticles.

It is authorized for use at some level in many countries.

On 15 March 2021, Moderna's second COVID-19 vaccine started phase I clinical trials. This vaccine candidate can potentially be kept in refrigerators instead of freezers, making distributions easier especially in developing countries.

Medical uses
The Moderna COVID-19 vaccine is used to provide protection against infection by the SARS-CoV-2 virus in order to prevent COVID-19.

The vaccine is given by intramuscular injection into the deltoid muscle. The initial course consists of two doses. The World Health Organization recommends an interval of 28 days between doses. Data show that first dose efficacy persists for up to ten weeks. Therefore, to avoid deaths where supplies are limited, the WHO recommends delaying the second dose by up to 12 weeks to achieve high coverage of the first dose in high-priority groups.

There is no evidence that a third booster dose is needed to prevent severe disease in healthy adults. A third dose can be added after 28 days for immunocompromised people in some countries.

Efficacy
Cumulative Incidence Curves for the First COVID-19 Occurrence Evidence of vaccine efficacy starts about two weeks after the first dose. High efficacy is achieved with full immunization, two weeks after the second dose, and was evaluated at 94.1%: at the end of the vaccine study that led to emergency authorization in the US, there were eleven cases of COVID-19 in the vaccine group versus 185 cases in the placebo group . Moreover, there were zero cases of severe COVID-19 in the vaccine group, versus eleven in the placebo group. This efficacy has been described as 'astonishing' and 'borderline historic' for a respiratory virus vaccine, and it is similar to the efficacy of the Pfizer–BioNTech COVID-19 vaccine.

Efficacy estimates were similar across age groups, sexes, racial and ethnic groups, and participants with medical comorbidities associated with high risk of severe COVID-19. Only individuals aged 18 or older were studied. Studies are underway to gauge efficacy and safety in children aged 0–11 and 12–17 .

A further study conducted by the US Centers for Disease Control and Prevention between December 2020, and March 2021, on nearly 4 thousand health care personnel, first responders, and other essential and frontline workers concluded that under real-world conditions, mRNA vaccine effectiveness of full immunization was 90% against SARS-CoV-2 infections, regardless of symptoms, and vaccine effectiveness of partial immunization was 80%.

The duration of protection provided by the vaccine is unknown as of April 2021, and a two-year followup study is underway to determine the duration.

Preliminary results from a Phase III trial indicate that vaccine efficacy is durable, remaining at 93% six months after the second dose.

The high efficacy of the vaccine already after the first dose, the observation that its immunogenicity even at quarter or half of the standard dose is substantial and the observed dose-side effect relationship has led to personalized vaccination concepts: Epidemic modelling using Moderna vaccine characteristics predicts that in a setting of limited vaccine availabilty, when a wave of virus Variants of Concern hits a country, the societal benefit of vaccination may be enhanced and accelerated by a personalized dosing strategy, adapted to the state of the pandemic, country demographics, age of the recipients, availability of vaccines, and individual risk for severe disease.

Using standard dosing in the elderly will reduce severe disease and deaths as shown in the pivotal study, reduced dosing in the healthy young that drive the pandemic spread through frequent social contacts may stop the pandemic earlier while still eliciting a sufficient immune response, and giving an additional booster dose to the immunosuppressed may optimize vaccine efficacy in this subpopulation known for weak immune response to vaccination.

Effectiveness
A vaccine is generally considered effective if the estimate is =50% with a >30% lower limit of the 95% confidence interval. Effectiveness is generally expected to slowly decrease over time.

Preliminary data from a study in Minnesota suggest that the vaccine remains effective against hospitalization and asymptomatic infection by the Delta variant. From January to July 2021, the dominant variant in Minnesota shifted from Alpha in January, with a prevalence of 85%, to Delta in July, with a prevalence of 70%. Effectiveness against hospitalization by any variant fell slightly, from 92% over the entire period to 81% in July. Effectiveness against asymptomatic infection by any variant also fell only slightly, from 86% over the entire period to 76% in July. By comparison, effectiveness against asymptomatic infection by any variant fell further for the Pfizer–BioNTech vaccine, from 76% over the entire period to 42% in July.

On 27 August, the Centers for Disease Control and Prevention published a study reporting that the effectiveness against infection decreased from 91% to 66% when the Delta variant became predominant in the US, which may be due to unmeasured and residual confounding related to a decline in vaccine effectiveness over time.

Specific populations
Limited data are available on the safety of the Moderna COVID-19 vaccine for people who are pregnant. The initial study excluded pregnant women or discontinued them from vaccination upon a positive pregnancy test. Studies in animals found no safety concerns and clinical trials are underway to evaluate the safety and efficacy of COVID-19 vaccines in pregnant people. Real-world observations through the CDC v-safe tracking program have not uncovered unusual numbers of adverse events or outcomes of interest. Based on the results of a preliminary study, the US CDC recommends that pregnant people get vaccinated with the COVID-19 vaccine.

Adverse effects
The World Health Organization stated that 'the safety data supported a favorable safety profile' and that the vaccine's AE profile 'did not suggest any specific safety concerns'. The most common adverse events were pain at the injection site, fatigue, headache, myalgia , and arthralgia .

The US Centers for Disease Control and Prevention has reported anaphylaxis in 2.5 cases per million doses administered and has recommended a 15-minute observation period after injection. Delayed cutaneous reactions at injection sites resulting in rash-like erythemas have also been observed in rare cases but are not considered serious or contraindications to subsequent vaccination. The incidence rate for local adverse erythema is about 10.8%, in 1.9% of cases redness may extend to a size of 100mm or greater.

On 23 June 2021, the US CDC confirmed that myocarditis or pericarditis occurs in about 13 of every 1 million young people, mostly male and over the age of 16, who received the Moderna or the Pfizer–BioNTech vaccine. Most affected individuals recover quickly with adequate treatment and rest.

Pharmacology
Moderna's technology uses a nucleoside-modified messenger RNA compound codenamed mRNA-1273. Once the compound is inside a human cell, the mRNA links up with the cell's endoplasmic reticulum. The mRNA-1273 is encoded to trigger the cell into making a specific protein using the cell's normal manufacturing process. The vaccine encodes a version of the spike protein with a modification called 2P, in which the protein includes two stabilizing mutations in which the original amino acids are replaced with prolines, developed by researchers at the University of Texas at Austin and the National Institute of Allergy and Infectious Diseases' Vaccine Research Center. Once the protein is expelled from the cell, it is eventually detected by the immune system, which begins generating efficacious antibodies. The mRNA-1273 drug delivery system uses a PEGylated lipid nanoparticle drug delivery system.

Chemistry
The active ingredient is an mRNA sequence containing a total of 4101 nucleotides that encodes the full-length SARS-CoV-2 spike glycoprotein, with two mutations designed to stabilize the pre-fusion conformation. The sequence is further optimized by:

all uridines substituted with N1-methylpseudouridine , flanked by an artificial 5' untranslated region and a 3' UTR derived from the human alpha globin gene , introduction of two additional stop codons, terminated by a 3' poly tail. A putative sequence of the vaccine has been published on a forum for professional virologists, obtained by direct sequencing of residual vaccine material in used vials.

The vaccine mRNA is dissolved in an aqueous buffer containing tromethamine, tromethamine hydrochloride, sodium acetate, and sucrose. The mRNA is encapsulated in lipid nanoparticles that stabilize the mRNA and facilitate its entry into cells. The nanoparticles are manufactured from the following lipids:

1,2-distearoyl-sn-glycero-3-phosphocholine
cholesterol
PEG2000-DMG 2000-dimyristoyl glycerol
SM-102
Manufacturing

Moderna is relying extensively on contract manufacturing organizations to scale up its vaccine manufacturing process. The first step of the process—synthesis of DNA plasmids —has been handled by a contractor called Aldevron based in Fargo, North Dakota. For the remainder of the process, Moderna contracted with Lonza Group to manufacture the vaccine at facilities in Portsmouth, New Hampshire in the United States, and in Visp in Switzerland, and purchased the necessary lipid excipients from CordenPharma. Besides CMOs, Moderna also manufactures the vaccine at its own production facility in Norwood, Massachusetts.

For the tasks of filling and packaging vials , Moderna entered into contracts with Catalent in the United States and Laboratorios Farmacéuticos Rovi in Spain. In April 2021, Moderna expanded its agreement with Catalent to increase manufacturing output at the latter's plant in Bloomington, Indiana. The expansion will allow Catalent to manufacture up to 400 vials per minute and fill an additional 80 million vials per year. Later that month, Moderna announced its plans to spend billions of dollars to boost production of its vaccines, potentially tripling the output in 2022, claiming as well that it would make no less than 800 million doses in 2021. The increase in production is in part attributed to improvements made by the company in manufacturing methods.

The Moderna news followed preliminary results from the Pfizer-BioNTech vaccine candidate, BNT162b2, with Moderna demonstrating similar efficacy, but requiring storage at the temperature of a standard medical refrigerator of 2–8 °C for up to thirty days or -20 °C for up to four months, whereas the Pfizer-BioNTech candidate requires ultracold freezer storage between -80 and -60 °C . Low-income countries usually have cold chain capacity for only standard refrigerator storage, not ultracold freezer storage. In February 2021, the restrictions on the Pfizer vaccine were relaxed when the US Food and Drug Administration updated the emergency use authorization to permit undiluted frozen vials of the vaccine to be transported and stored at between -25 and -15 °C for up to two weeks before use. The vaccine should not be stored at a temperature below -50 °C .

In November 2020, Nature reported that 'While it's possible that differences in LNP formulations or mRNA secondary structures could account for the thermostability differences , many experts suspect both vaccine products will ultimately prove to have similar storage requirements and shelf lives under various temperature conditions.'

History
In January 2020, Moderna announced development of an RNA vaccine, codenamed mRNA-1273, to induce immunity to SARS-CoV-2.

Moderna received US$955 million from BARDA, an office of the US Department of Health and Human Services. BARDA funded 100% of the cost of bringing the vaccine to FDA licensure.

The United States government provided US$2.5 billion in total funding for the Moderna COVID-19 vaccine . Private donors also made contributions to the vaccine's development. The Dolly Parton Covid-19 Research Fund contributed with US$1 million.