Spike protein production by mRNA vaccines?

Spike protein production by mRNA vaccines?

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I am trying to understand the spike protein production mechanism of the mRNA vaccines, and during my research I learned that the mRNA (Moderna, mRNA-1273) vaccines hijack the cell machinery to produce spike proteins of SARS-CoV-2 by providing genetic material mRNA (which is encapsulated by lipid nanoparticle).

My question, which cells are subject to the vaccine particules (which factor determines the target cells?) Are produced spike proteins part of the cells (which interacted by the vaccine), or are these proteins emitted into the bloodstream like hormones so immune systems attack only the produced spike proteins?

I am asking this question to understand whether the cells which are used to create spike proteins are attacked by the immune system.

I am asking this question to understand whether the cells which are used to create spike proteins are attacked by the immune system.

Yes, that is the aim of RNA vaccinations!

But don't worry, that's a good thing, as can be concluded from this review-paper, that emphasizes the advantage of RNA vaccinations to invoke cellular immune response:

Although subunit vaccines have been used successfully to elicit humoral immunity against a wide variety of pathogens, they fail to induce cellular immunity which is required to eradicate the intracellular pathogen reservoir of many chronic diseases, including viral infections such as HIV or hepatitis C.

Basically, the idea is that presented antigens from traditional vaccines are inclined to be presented via MHC2, rather causing humoral immunity, while after RNA transfection, cellularly produced peptides can also be presented on MHC1, causing cellular immunity.

The efficacy trial enrolled some 40,000 people, about 75% in Latin America and 25% in Europe. The topline finding came from an interim analysis evaluating 134 participants who developed at least one COVID-19 symptom. Although the company did not give a breakdown, the reported 47% efficacy translates to roughly 88 cases in the placebo group and 46 among the vaccinated. “The results are sobering,” said Franz-Werner Haas, CureVac’s CEO.

He stressed that the many SARS-CoV-2 variants now in circulation may explain the disappointing results. The vaccine’s mRNA was designed for a version of spike that was dominant among viruses early in the pandemic but has evolved through multiple mutations. “We are virtually fighting a different virus, different pandemic over the last 6 months,” Haas said.

The trial scientists sequenced the virus in 124 participants who got sick and found 13 different variants. Only 1% of the infected people had a SARS-CoV-2 whose spike matched the mRNA used in the vaccine. “Demonstrating high efficacy in this unprecedented broad diversity of variants is quite challenging,” Haas said.

Other efficacy trials have found that certain mutant strains of the coronavirus can compromise the ability of COVID-19 vaccines to protect against mild disease, but the variant that has most powerfully undermined other vaccines, Beta, was not seen in the CureVac study. In contrast, Alpha, first seen in the United Kingdom and one of the earliest variants of concern, caused 41% of the 124 cases overall and 91% of the 44 cases that occurred in Europe.

Kathleen Neuzil of the University of Maryland School of Medicine doubts variants fully explain the poor performance of CureVac’s vaccine. Unlike CureVac’s mRNA shot, she says, the Pfizer-BioNTech and Moderna vaccines “work very well against Alpha.” She cautions that it’s difficult to compare trials of different vaccines, but says, “It’s just hard for me to believe that the variants could have this degree of effect.”

CureVac did not provide any data about how many of the infected in its efficacy trial developed severe disease. Other vaccines continue to prevent most hospitalizations and deaths even when variants reduce their protection against mild COVID-19.

Some scientists trying to make sense of the CureVac result point to an earlier, phase 1 study of the vaccine. It showed that serum levels of so-called neutralizing antibodies, which prevent the virus from binding to cells, were relatively low in vaccine recipients compared with people who naturally became infected with the coronavirus. “It’s certainly a good possibility that the vaccine is just not immunogenic enough,” says John Moore, an immunologist at Weill Cornell Medicine who specializes in analyzing neutralizing antibodies.

The type of mRNA used by CureVac may undermine antibody formation, contends Drew Weissman of the University of Pennsylvania’s Perelman School of Medicine, who helped pioneer certain mRNA modifications used in the Pfizer-BioNTech and Moderna vaccines. (Those companies license the technology, which may financially benefit the university and Weissman.) CureVac’s vaccine used an unmodified form of mRNA. When natural mRNA is injected into the body, it triggers the production of interferons, signaling molecules that can rev up the immune system. CureVac touted that as an advantage of its formulation. But Weissman notes interferons can also block the generation of T helper cells that, in turn, direct B cells to make antibodies.

Pfizer and BioNTech and Moderna, in contrast, chemically altered the uracils, one of the four nucleotides that make up RNA, in their spike-encoding sequences. Weissman’s group had shown in 2018 that uracil-modified mRNA triggered potent neutralizing antibodies and other protective immune responses in animal models. He notes that a BioNTech study comparing modified and natural mRNA vaccines also found that the modifications boosted the antibody response.

Peter Kremsner of University Hospital Tübingen, who helped run the CureVac study, suggests another factor: too low a dose of vaccine. “I am uncertain what it was finally, natural uracil or only dose or both,” he says. Kremsner helped conduct CureVac’s phase 1 study, which compared the safety and immune responses generated by doses between 2 and 20 micrograms. The study revealed the company should not use the higher doses “because of intolerability, perhaps due to natural uracil?” he says. (Kremsner says he hopes to publish his work soon, but a preprint with some of the study’s data has already been posted.) CureVac settled on 12 micrograms, a dose that balanced the best safety profile with the highest level of neutralizing antibodies. (The Pfizer-BioNTech vaccine uses a 30-microgram dose and Moderna’s is 100 micrograms.)

Other data presented at yesterday’s press conference suggest, however, that the design of the vaccine is more important than the dose. CureVac reported data from a monkey study that compared its current vaccine to a next-generation version, which is more stable inside of cells and made in collaboration with the pharmaceutical giant GlaxoSmithKline: The new candidate produced higher levels of the spike protein, triggering a 10-fold higher level of neutralizing antibodies. Dose-ranging studies of the Pfizer and Moderna vaccines have also found that higher mRNA doses offer relatively modest gains in antibody levels.

Still, CureVac says it must wait for the final analysis of the current efficacy trial, expected to include more than 200 COVID-19 cases, before it makes a “strategic shift” to the second-generation vaccine. “For now, we are going full speed exactly where we are,” Haas said. “We are expecting the data to come within the next 3 weeks.”

Dr. Garman explains how COVID-19 mRNA vaccines work

UPDATE: The FDA authorized a third COVID-19 vaccine in late February.

So far, the Food and Drug Administration has authorized two COVID-19 vaccines — the Pfizer-BioNTech COVID-19 vaccine and the Moderna COVID-19 vaccine​​ — which are both messenger ribonucleic acid or mRNA vaccines.

The Centers for Disease Control (CDC) describes these mRNA vaccines as containing instructions for your cells on how to make a piece of the “spike protein” that is unique to COVID-19. That protein triggers an immune response inside our bodies, producing antibodies and activating T-cells to fight off what it thinks is an infection. This protects us from getting infected if the real virus enters our bodies. The CDC points out that mRNA vaccines do not use the live virus that causes COVID-19.

NDWorks asked Dr. Ben Garman , medical director at the Notre Dame Wellness Center, to explain how mRNA vaccines work.

“An mRNA vaccine works a little differently than most other vaccines that are available to us, such as a more traditional mechanism of vaccination for the measles or the flu or chickenpox. Typically, those either use a weakened, killed or a picked-apart copy of the virus that won’t normally cause you to contract disease, but it's similar enough to the real virus or bacteria that your body mounts an immune response to the real version.

“The way these new mRNA vaccines work is the mRNA molecule is surrounded by a lipid shell or kind of a chunk of fat, and all that chunk of fat does is allow that mRNA molecule to enter your cells, otherwise mRNA can't get past the membrane. And once it's there, your body reads that mRNA and uses its natural machinery to produce a specific protein that would naturally be on the virus that you are vaccinating against — in this case, the spike protein, which a lot of people have probably heard of for COVID. Your body naturally recognizes that spike protein, after your cell makes it, as something bad. And it makes a bunch of immune responses to that spike protein without you ever having to have the virus inside your body .

“. mRNA vaccines have a lot of benefits compared to traditional mechanisms. One of those benefits (to scientists and doctors) is that all you need to start working on (the vaccine) is the genetic code of the virus. And that genetic code was known by December of 2019. And so (scientists and doctors) could start producing potential variations of this vaccine even before 2020 started, and they did. Moderna, specifically, is a company founded to make mRNA vaccines, and so this is all they do. This is the first commercial mRNA vaccine, but it's not the first mRNA vaccine that they've ever tried or have done research on. It's still a relatively new form of technology, but this is not the first. This is just the first one that is for commercial use.”

Dr. Garman points out that mRNA vaccines will not affect your DNA.

“It's not going to change your genetic material. It's just that temporary blueprint. And then using the natural mechanisms of your body, you then produce a specific protein that's normally on the virus,” he said.

A network analysis of COVID-19 mRNA vaccine patents

A preliminary network analysis highlights the complex intellectual property landscape behind mRNA-based COVID-19 vaccines.

The COVID-19 pandemic has had a substantial impact on global health and highlighted the importance of international cooperation to effectively combat SARS-CoV-2. Since the discovery and publication of the virus’s genome in January 2020, scientists have rushed to develop vaccines, therapeutics and diagnostics on an unprecedented timescale. To date there are 80 vaccines in clinical trials and 70 more in clinical development, setting the stage for some of the fastest vaccine development and testing in modern history 1 . The vaccine technology platforms used by the most promising vaccine candidates range from viral vector–based and protein-based technologies to mRNA and lipid nanoparticle technology. Despite these impressive scientific achievements, barriers such as the vaccine cold chain and multiple forms of intellectual property (IP) protection stand in the way of equitable access and fair allocation.

Webs of intellectual property claims underpin the marketing of many vaccines. For example, the underlying technology used to develop a vaccine can be protected by patents, while manufacturing methods and techniques (know-how) can be protected by trade secrets. Therapeutic development programs tend to consist of an intricate relationship between an inventor and an innovator 2 . The foundational technology needed to develop a vaccine could have been invented in an academic lab setting or startup research firm, protected through patents, and subsequently licensed out to a larger entity for further development and commercialization. These larger entities are designated as innovators because they transform the foundational technology into the final market product. In an attempt to demonstrate the complexity involved in IP protections and licensing deals surrounding COVID-19 vaccine technology, we developed a preliminary patent network analysis. We identified patents that were relevant to various vaccine technology platforms and used US Securities and Exchange Commission (SEC) filings to highlight pertinent licensing deals. A visualization of the landscape is shown in Fig. 1.

Large nodes represent the relevant entities while the edges represent agreements or patents between two entities. Smaller nodes around the entities represent patents that were identified as being relevant to the underlying vaccine technology (Supplementary Information). The network analysis was developed using Gephi 23 . UPenn, University of Pennsylvania UBC, University of British Columbia app., application.

Moderna, Pfizer and BioNTech, CureVac and Arcturus have all developed mRNA-based vaccine candidates for COVID-19. This vaccine technology platform uses mRNA technology, lipid nanoparticle technology and delivery system technology to achieve a desired biological response. A lipid nanoparticle must be used to deliver the mRNA to the cells to avoid mRNA degradation, which makes it a key aspect of the vaccine’s technology. After the mRNA is delivered to a cell, it instructs the cell to produce the SARS-CoV-2 spike protein, thereby eliciting an immune response 3,4 .

Scientists have studied the use of mRNA as a novel therapeutic since the early 1990s 5 . However, it wasn’t until 2005 that a group of researchers at the University of Pennsylvania published findings on mRNA technology that have since been deemed critical to the development of mRNA based therapies 6 . SEC filings highlighted by Knowledge Ecology International reveal a series of sublicenses for mRNA-related patents that stem from the University of Pennsylvania to both Moderna and BioNTech 7,8,9 . The 2017 filings indicate that the University of Pennsylvania exclusively licensed their patents to mRNA RiboTherapeutics, which then sublicensed them to its affiliate CellScript. CellScript proceeded to sublicense the patents to Moderna and BioNTech however, the patent numbers are redacted in all the filings, making it difficult to determine which are relevant to the production of COVID-19 vaccines.

Another key aspect of an mRNA vaccine platform is the ability to deliver the mRNA to a cell using a lipid nanoparticle. Some early work on lipid nanoparticles was done jointly by the University of British Columbia and Arbutus Biopharmaceuticals in 1998. SEC filings show that patents relating to this early technology were solely assigned to the University of British Columbia and then licensed back to Arbutus 10 . Further analysis reveals that in 2012 Arbutus licensed a set of patents relating to the delivery of nucleic acids to Acuitas Therapeutics. In 2016, Acuitas entered into a development and option agreement with CureVac, which included access to patents on lipid nanoparticle technology 11 . Acuitas also granted a sublicense to Moderna however, in 2016 Arbutus declared that Acuitas’s sublicense to Moderna was improper and took to the Canadian legal system for remedy 10 . The litigation in Canada was eventually settled, but in 2018 Moderna began filing inter partes reviews (IPR), a procedure for challenging the validity of a US patent before the US Patent and Trademark Office, on three of Arbutus’s patents, which concluded with the cancellation of claims in two of the three challenges 12 . Moreover, Arbutus also entered into an agreement with Roivant to spin out Genevant, which received a license for the patent portfolio on lipid nanoparticles 13 . Genevant sublicensed the patents to BioNTech, who then entered into an agreement with Pfizer to develop a COVID-19 vaccine 14,15,16 . It is also important to note that the US National Institutes of Health (NIH) and Moderna entered into an agreement in 2019 to co-develop coronavirus vaccines however, this was before the identification and spread of SARS-CoV-2 17,18 .

The mRNA vaccine platform for COVID-19 relies on the production of the coronavirus spike protein to elicit an immune response. Moderna, CureVac, Pfizer and BioNTech have all disclosed that the mRNA used in their vaccine candidates encodes a stabilized version of the spike protein that was developed by the NIH. A report by Public Citizen identified a pending patent application on this modified spike protein that was filed by the NIH 19 . The NIH also has four other provisional patent applications on a novel coronavirus vaccine as disclosed in a recent publication 17 . This complex matrix of patents, licenses and agreements between these entities highlights the intricacies involved in biopharmaceutical development. Since patent numbers are redacted in all the SEC filings, we decided to develop our own patent landscape for the respective entities. Patents and patent applications that are relevant to the respective vaccine technology platform and owned or assigned to any of the entities discussed were identified and highlighted (Supplementary Information) 20,21 . A visual representation of the science encompassed in the patents and applications is shown in Fig. 2 22 .

The scientific landscape was developed using VOS Viewer. LNP, lipid nanoparticle NME, new molecular entity PEG, polyethylene glycol PKR, protein kinase R SEQ ID, sequence identifier 3UTR, 3′ untranslated region.

The success of mRNA vaccines in clinical trials highlights the potential of mRNA technology to be the future of medicine. The rapid development and clinical success of COVID-19 mRNA vaccines can be credited to the relationship between inventors and innovators. As evidenced by our network analysis, key technological advancements were invented in academic labs or small biotech companies and then licensed to larger companies for product development. Despite this success, patents, trade secrets and know-how owned by or assigned to larger companies may impede future research and development of mRNA technology by creating legal barriers that limit access to this technology.

Spotting the Intruder

When a vaccinated cell dies, the debris will contain many spike proteins and protein fragments, which can then be taken up by a type of immune cell called an antigen-presenting cell.

The cell presents fragments of the spike protein on its surface. When other cells called helper T cells detect these fragments, the helper T cells can raise the alarm and help marshal other immune cells to fight the infection.

MRNA vaccine

Truly an innovative vaccine strategy, mRNA vaccines are easier to make compared to traditional vaccines. It also has a higher efficacy as mRNA vaccines make the host cells produce the protein, which is more stable than traditional vaccines that introduce the protein into the body.

But mRNA vaccines are new, lacking a long-term safety profile. Currently, clinical trials only have safety data for at least two months.

One argument supporting the long-term safety of mRNA vaccines is that mRNA genetic material is incredibly fragile, to the point where such vaccines have a strict storage condition at -20 to -80°C coldness. At least in animal experiments, the mRNA in mRNA vaccines got degraded within 48 hours. As follows, the mRNA-coded proteins only got produced and expressed for about 48 hours. So, common side effects of mRNA vaccines — such as fatigue, myalgia, or headache —only last for 1–2 days.

SARS-CoV-2 Spike Protein Elicits Cell Signaling in Human Host Cells: Implications for Possible Consequences of COVID-19 Vaccines

The world is suffering from the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). SARS-CoV-2 uses its spike protein to enter the host cells. Vaccines that introduce the spike protein into our body to elicit virus-neutralizing antibodies are currently being developed. In this article, we note that human host cells sensitively respond to the spike protein to elicit cell signaling. Thus, it is important to be aware that the spike protein produced by the new COVID-19 vaccines may also affect the host cells. We should monitor the long-term consequences of these vaccines carefully, especially when they are administered to otherwise healthy individuals. Further investigations on the effects of the SARS-CoV-2 spike protein on human cells and appropriate experimental animal models are warranted.

Keywords: COVID-19 SARS-CoV-2 cell signaling coronavirus spike protein vaccine.

Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study in the collection, analyses, or interpretation of the data in the writing of the manuscript or in the decision to publish the results.

A Deep Dive On mRNA Vaccines

February 11, 2021 | Messenger RNA (mRNA) vaccines were the focus of a symposium on COVID-19 vaccines held during last week&rsquos COVID-19 and Cancer virtual meeting of the American Association for Cancer Research. To date, only two vaccines have received Emergency Use Authorization by the U.S. Food and Drug Administration and both are mRNA vaccines&mdashone developed by Moderna and the other by Pfizer and BioNTech.

Speaking on development of the Moderna vaccine was Randall N. Hyer, M.D., Ph.D., the company&rsquos senior vice president of global medical affairs. Michela Locci, Ph.D., assistant professor of microbiology at the University of Pennsylvania, presented on the ability of mRNA vaccines to elicit potent germinal center (GC) responses associated with neutralizing antibody generation. This was followed by a lively Q&A session moderated by Deepta Bhattacharya, Ph.D., a member of the cancer biology program at the University of Arizona Cancer Center.

Moderna&rsquos COVID-19 vaccine development program utilizes an advanced mRNA technology platform also being used to develop other medicines and vaccines, says Hyer. The approach uses DNA to make mRNA that instructs cells to make a harmless piece of the spike protein found on the surface of the virus, triggering an immune response and the production of antibodies.

The vaccine does not alter DNA, he says. It also does not signal for nuclear access or reverse transcription. It contains no adjuvant at all, says Hyer. Rather, the vaccine appears to trigger the innate immune system.

At the lymph node, B cells (derived from the bone marrow) and T (thymus) cells interact with the spike protein and develop an adaptive immune response, he explains. Once the mRNA and protein it produces have done their job, they degrade after a day or two.

The vaccine has been produced in large quantity and formulated with lipid nanoparticles that are 100 nanometers in diameter, Hyer continues. In animal models, it demonstrated robust COVID-19 neutralizing antibody response and prevented the replication of the virus in the airways.

Adaptive Trial Design

Phase 1, 2, and 3 clinical studies overlapped to accelerate the traditional vaccine timeline, says Hyer. Convalescent serum from 41 individuals diagnosed with COVID-19 was used as a comparator, and participants ranged in age from 20 to 77 years. Antibody levels were detected and &ldquodeclined very little,&rdquo and remained elevated for three months after a second booster shot.

The geometric mean titer and T-cell response &ldquolooked good&rdquo after the first dose, he says. &ldquoBut it took a second dose to get above the levels of convalescent serum, so the booster is important.&rdquo

In trials, the second dose was administered about 28 days after the first but the &ldquoimmunization window&rdquo extended out another 10 days. The maximum acceptable delay in receiving the second dose is unknown, says Hyer. Other multi-dose vaccines typically have a firm minimum interval, he adds, &ldquobut we&rsquore in new territory here.&rdquo

In the phase 3 trial with 30,000 U.S. participants, randomized 1:1 to two shots of the vaccine or placebo, Moderna&rsquos mRNA vaccine showed 94.1% efficacy overall with tight confidence intervals, says Hyer. Participants included individuals at risk of developing severe COVID-19 based on their age and comorbid conditions. Individuals 18-65 without comorbid conditions comprised 17% of the study population, people 18-65 with comorbid condition 17%, and those 65 and up (with and without comorbid conditions) 25%.

Vaccine efficacy remained &ldquovery high&rdquo for different racial groups, but case numbers were too small to calculate conclusively, Hyer adds. Importantly, there was no evidence of vaccine-associated enhanced respiratory disease. Cases of severe COVID-19 numbered 30 in the placebo group compared to zero for those in the vaccine group.

Mortality was lower among individuals in the placebo group than the population at large and, most notably, the elderly. The reason, Hyer says, is that study participants were &ldquomore sensitive to basic public health precautions, and we followed up on them.&rdquo

Systemic reactions to the vaccine&mdashprimarily pain at the injection site and flu-like symptoms&mdashwere higher after the second injection and each was more common among younger participants, reports Hyer. Some of those same ill effects were seen in the placebo group. Unsolicited adverse events were roughly the same in the placebo and vaccine groups.

Follow-up Studies

As recently announced by Moderna, in vitro neutralization studies indicate that the vaccine retains its neutralizing action against emerging variants, including those from South Africa (B.1.351), the U.K. (B.1.1.7), and Brazil (P.1), adds Hyer, but new studies are planned. It provides a similar level of immune protection against these new variants as it does the original Wuhan strain.

The company is also testing two different booster vaccines aimed at the concerning B.1.351 strain, Hyer says. Antibody levels produced by the Moderna vaccine, while above levels expected to be protective, were about six times lower with B.1.351 than prior variants.

If a variant emerges that becomes the dominant strain in circulation, using a mix of vaccines might be considered. &ldquoAll options are on the table,&rdquo says Hyer. Unlike the 1918 pandemic, the second and faster moving wave of infection with SARS-CoV-2 is unlikely to end after a few months, even if COVID-19 and influenza are both mRNA viruses.

Moving forward, Moderna also plans to collect additional data specific to children, cancer patients, and pregnant women, all of whom were excluded from the initial round of clinical trials, he says. For the effects in cancer patients, Moderna is partnering on a study with the National Cancer Institute.

&ldquoWe felt it was important to have as clean a look [as possible] at immunogenicity offered by the vaccine, says Hyer, noting that immunosuppressed people are typically not enrolled in vaccine trials. However, the Moderna trial included 176 people with HIV, among whom no unusual safety concerns were reported.

Memory B Cells

The race to come up with a safe and efficacious COVID-19 vaccine has had many contenders, including 173 candidates in preclinical studies and 63 vaccine candidates in clinical development, says Locci. Among them are RNA and DNA vaccines, recombinant protein vaccines, inactivated vaccines, and live attenuated vaccines.

The spike protein is the target of both the Moderna and Pfizer/BioNTech mRNA vaccines, and the receptor-binding domain (RBD) it contains is an ideal candidate for vaccine development, Locci says. While the immune cellular responses to mRNA vaccination is known to be good, she has endeavored to fill the information gap on the magnitude and quantity of memory B cells they generate.

As detailed in a recently published study in Immunity (DOI: 10.1016/j.immuni.2020.11.009), two SARS-CoV-2 mRNA vaccines&mdashbut not a recombinant protein vaccine formulated with the MF59-like adjuvant AddaVax&mdashpromote robust GC-derived immune responses in mice, she says. These include GC B and T follicular helper (Tfh) cell responses as well as long-lived plasma cells and memory B cells&mdashall of which strongly correlated with neutralizing antibody production.

RBD-specific GC B cells peaked at seven days and fell a week later and induced the potent GC reaction. For at least 60 days post-immunization, immunoglobulin G (IgG) antibodies that are expressed by B cells were also significantly higher. The Tfh cells elevated by the mRNA vaccines also had stronger Th2 polarization, says Locci, which plays a key role in maintaining the delicate balance between antigen responsiveness and tolerance.

Locci speculates that memory B cells drive a secondary GC response with the second shot of the mRNA vaccines since they tend not to re-enter the germinal center upon boost.

Many Unknowns

The two hot topics discussed during the final Q&A session were transmissibility of the virus post-vaccination and how long to wait between the first and second doses.

To answer the transmission question, researchers will need to look for penetration of IgG nodes in the respiratory airways of larger animal models, says Locci. But she suspects this is the case, given the vaccine&rsquos cellular presence is transient.

Up to 30% of infected individuals are asymptomatic, which would explain the rapid spread of COVID-19, Hyer says. With the SARS-CoV-1 in 2003, it was clear who was infected so they could be isolated. &ldquoWe could shut it down after 840 cases. Now we see 840 cases before lunch, or more.&rdquo

An interesting finding from clinical trials for the Moderna vaccine was that 39 individuals in the placebo group and 15 in the vaccine group who were PCR negative for SARS-CoV-2 at baseline had nasopharyngeal swabs that were positive for the virus at the second dose but had no evidence of COVID-19 symptoms, says Hyer.

The implication is that even one dose of the vaccine could potentially reduce asymptomatic cases, which will need to be confirmed by larger follow-up studies. &ldquoIf we can get a grip on any of the effects vaccination has on transmission of asymptomatic infection, that would be huge,&rdquo says Hyer.

As to the mechanism of early protection seen with the Moderna vaccine at around 14 days after the first dose, Locci points to antibodies as a contributing force. In mice as early as day seven, the vaccine produced robust (if short-lived) plasma cells, she says.

Hyer&rsquos thought is that the mRNA technique has a &ldquomore pronounced effect upstream, turning the body into an in vivo vaccine antigen production [factory].&rdquo Some innate effects may simultaneously be taking place, he adds. &ldquoWe don&rsquot know.&rdquo

Interferon may be an &ldquoimportant player,&rdquo says Locci, indicating that this will be studied shortly.

&ldquoThe mRNA vaccine may just be a potent inducer of innate immunity,&rdquo adds Hyer.

&ldquoThe mRNA component is important, but the real star is lipid nanoparticles,&rdquo Locci says. A soon-to-publish study will show that they are &ldquoalmost as good&rdquo as vaccine themselves at prompting an immune response.

In reply to questions regarding the interval between first and second vaccine doses of the Moderna vaccine, Hyer says it would be &ldquofolly&rdquo to assume knowledge from previous vaccines could be applied to this one. &ldquoIt may very well be the second dose needs to occur within that [10-day] window&rdquo used in clinical trials.

&ldquoWhat&rsquos striking is that two different efforts to develop prophylactic vaccination using a similar strategy but a different vaccine, different manufacturer, different lipids, and different populations had their point efficacy within 1% [of each other],&rdquo Hyer says.

In the absence of clinical data on immunocompromised patients on therapies for cancer, &ldquoit is up to individual doctors&rdquo to decide if the benefit of vaccination outweighs the risks, says Hyer. The only contraindication to the Moderna vaccine is anaphylaxis to the vaccine itself, he adds.

Even if patients&rsquo antibody response is expected to be suboptimal, adds Locci, odds are good that an mRNA vaccine will produce CD4 (helper) and CD8 T (cytotoxic) cells. While both the Moderna and Pfizer vaccines trigger strong CD4 T-cell responses, Pfizer&rsquos vaccine has been shown to elicit a more robust CD8 T-cell response, she says.

An advantage of vaccine delivery via lipid nanoparticles, relative to traditional approaches, may be that mRNA expresses the full-length spike protein and is a &ldquonatural process in the antigen-presenting cell,&rdquo says Hyer. The mRNA platform endeavors to &ldquomimic natural infection processes, so I assume that has something to do with triggering innate response and other aspects of the immune system.&rdquo

Viral vector approaches face the possibility of anti-vector cellular immunity diminishing vaccine effectiveness, Hyer says, in reply to a question about their disadvantages.

MRNA Covid-19 Vaccines Are Fast to Make, but Hard to Scale

Jared S. Hopkins

Joel Eastwood

Dylan Moriarty

Pfizer Inc. and partner BioNTech SE did the unimaginable when they developed a Covid-19 vaccine in less than a year. Previously, the quickest vaccine development program was the four years it took to make the mumps vaccine, licensed in 1967.

A big reason for the speedy success: a new gene-based technology involving messenger RNA, the molecules that carry genetic instructions. Yet that technology has also complicated manufacturing, forcing companies to redo how shots get made.

Bottlenecks have emerged, manufacturing experts say, because some steps are difficult to scale up quickly or because they simply haven’t been done before.

mRNA vaccines instruct cells to make a harmless version of the spike protein that juts from the new coronavirus. Production of the protein trains the immune system to recognize the real coronavirus—and fight it.

To make mRNA vaccines, Pfizer assembled a bespoke manufacturing network that the company projects will make 2 billion doses this year.

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