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Understanding mRNA vaccine for COVID

Understanding mRNA vaccine for COVID


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As I've learned, mRNA helps us to produce virus spikes proteins to induce learning of the immune system.

But then, I remember to have read that the coronavirus has some trick to pretend to be "food" to our cells, that is it has some lipid element. So it can entry the cell easily. But this was not same part as the spike protein, right? (otherwise it would have been contradictory with the mRNA approach?)


You have it wrong. Coronaviruses are part of a family of viruses that are called "enveloped viruses". These all have an "envelope" comprised of a lipid layer derived from the host cell as the virion exits. The envelope is distinct from the spike. The spike protein is produced by the virus during replication and is not found naturally in a host cell.

This does not pretend to be "food" at all, but it can help evade host immune responses by hiding the other virion capsid proteins.


The Application and Future Potential of mRNA Vaccines

Vaccines are often described as one of the greatest public health interventions in recent history, based on the profound effect that they have had in decreasing global morbidity and mortality. Immunizations currently prevent 2-3 million deaths each year, and aside from sanitation and clean drinking water, they are credited as having the largest impact on population growth and life expectancy. Vaccines have far-reaching health, social and economic benefits when they are broadly available and accessible.

Developing new vaccines, however, is not for the faint of heart. Vaccines traditionally take 10-20 years to develop, and research and testing costs can easily mount into the billions of dollars. So the natural question in light of the COVID-19 pandemic is: How were the currently available vaccines developed so quickly?

Three key factors contributed to the accelerated development of COVID-19 vaccines. First, there was unprecedented global collaboration through coordinated partnerships among governments, industry, donor organizations, nonprofits and academia. This sort of collaboration and coordination is not a minor feat, and it’s the only way we could have achieved what has been seen in the past year, as no one group could have done this alone. Second, there was significant upfront investment from national governments that reduced the financial risks associated with product development this allowed vaccine developers to conduct multiple steps in vaccine development in parallel, as opposed to sequentially. Third, major advances in vaccine technologies over the last 5-10 years greatly accelerated the development of vaccines for SARS-CoV-2, the virus that causes COVID-19.

It is the third factor in particular that unleashed the future potential of messenger RNA, or mRNA, vaccines, which is the platform adopted by both Pfizer-BioNTech and Moderna for their COVID-19 vaccines. Messenger RNA vaccine technology has been in development for over two decades, but only recently has it become mature enough for use against SARS-CoV-2. Unlike traditional viral vaccines – which may deliver an inactivated or weakened version of a virus or a piece of a virus, such as a specific protein, to stimulate an immune response – messenger RNA vaccines deliver genetic instructions for making a portion of the target virus to an individual’s cells. The body’s cells then make the protein needed to generate an immune response. Due to advances in this technology, scientists pursuing a COVID-19 vaccine were able to synthetically produce genetic material containing instructions for making a key SARS-CoV-2 virus protein and successfully generated an immune system response. This breakthrough ability presents new opportunities for creating future mRNA vaccines that are tailored to fight different infectious diseases. Other scientific advances over the last two decades, such as encapsulating the mRNA into fat molecules known as lipid nanoparticles (LNPs) to protect the molecule and enhance its delivery into cells, also bolstered the COVID-19 vaccines’ success.

The implications of mRNA technology are staggering. Several vaccine developers are studying this technology for deployment against rabies, influenza, Zika, HIV and cancer, as well as for veterinary purposes. Its potential utility is based upon its being a “platform technology” that can be developed and scaled rapidly. Given that only the genetic code for a protein of interest is needed, synthetically produced mRNA vaccines can be made rapidly, in days. Other vaccine approaches involve growing and/or producing proteins in cells, a process that can take months. Messenger RNA vaccines are generally regarded as safe, since they do not integrate into our cells’ DNA and naturally degrade in the body after injection. They also can be safely administered repeatedly, as we are seeing with the two-dose regimen for both the Pfizer-BioNTech and Moderna vaccines.

Despite the current success of mRNA vaccines for COVID-19, scientists continue to work on making the technology better. A number of laboratories are testing more thermostable formulations of mRNA vaccines, which currently must be kept at freezing or ultra-cold temperatures. Others are investigating second-generation vaccines that will only require a single shot, and “universal” coronavirus vaccines that could protect against future emerging coronaviruses. Messenger RNA vaccines that target a broad range of different diseases, all in one shot, are also in development this approach has the potential to greatly simplify current vaccination schedules.

Taken together, these advantages and potential future developments position mRNA vaccines as an increasingly important technology in our arsenal of tools against infectious disease outbreaks, and are likely to be critical to fighting future epidemics and pandemics. Global partnerships like the Coalition for Epidemic Preparedness and Innovation (CEPI), tasked with facilitating the development of vaccines to stop future epidemics, have called for vaccines to be able to be tested in the clinic within months after a new pathogen is identified. With the latest discoveries in mRNA technology, we are well on our way to this goal the ability of this platform technology to be transformative is no longer a hope, but more likely to be a reality in the very near future.

Swati Gupta, Dr.P.H., M.P.H. ’97, is vice president and head of emerging infectious diseases and scientific strategy at IAVI, a nonprofit scientific research organization that develops vaccines and antibodies for HIV, tuberculosis, emerging infectious diseases (including COVID-19) and neglected diseases.

This commentary is part of a series produced by Yale School of Public Health highlighting important issues related to COVID-19 and public health.


MRNA COVID vaccine is a first for humans

Forget polio, chicken pox, yellow fever &ndash even flu vaccines. The Coronavirus vaccines are like no other&mdashand that, in part, is why they were developed so quickly.

&ldquoThese are totally different than the vaccines we&rsquove had in the past,&rdquo according to Rad Moeller, a rheumatologist practicing with CarolinaEast Internal Medicine at Havelock and president-elect of the North Carolina Rheumatology Association.

Vaccines work by introducing the virus they are aimed to fight into your bloodstream. The earliest vaccine was developed by Edward Jenner in 1796. Smallpox was ravaging Europe and America &ndash a virus with a 30 percent kill rate. Survivors &ndash George Washington was one &ndash were left with scars as a memento of their deadly battle. Jenner noticed that farm girls in the country were somehow evading the deadly disease and realized they were developing immunity by association with cowpox &ndash a virus similar to smallpox but not nearly so deadly and carried by cows.

He scraped fluid from lesions on the women and introduced them into the bloodstream of healthy people. Their bodies fought off the mild disease and, as a result, learned to fight off its deadlier cousin, smallpox. End of the story? Stronger vaccines replaced the natural cowpox and today smallpox is the only virus that has been declared completely eradicated from the earth.

According to the CDC vaccines (including the COVID ones) prevent greatly reduce the risk of. infection by working with the body&rsquos natural defenses to safely develop immunity to the disease.&rdquo

Past vaccines imitate infections&mdashoften using an altered, harmless form of the deadly virus that causes the T-lymphocytes &ndash a kind of white blood cell &ndash to create antibodies to fight it.

But, according to Dr. Rad Moeller, a rheumatologist working with CarolinaEast Internal Medicine in Havelock, trying to modify the COVID virus in a facility is unwise because of how dangerous the virus is.

Moeller who is also a consulting professor of medicine at Duke University, knows what he is talking about. He has contacts at Moderna, one of the two companies that have developed the new vaccine, and has followed its development closely.

mRNA is a nucleic acid &ndash Moeller compared it to an instruction manual that teaches the cells how to fight COVID. As the CDC describes it:

&ldquomRNA can most easily be described as instructions for the cell on how to make a piece of the &ldquospike protein&rdquo that is unique to SARS-CoV-2. Since only part of the protein is made, it does not do any harm to the person vaccinated but it is antigenic.

&ldquoAfter the piece of the spike protein is made, the cell breaks down the mRNA strand and disposes of them using enzymes in the cell. It is important to note that the mRNA strand never enters the cell&rsquos nucleus or affects genetic material.

&ldquoThis information helps counter misinformation about how mRNA vaccines alter or modify someone&rsquos genetic makeup.

&ldquoOnce displayed on the cell surface, the protein or antigen causes the immune system to begin producing antibodies and activating T-cells to fight off what it thinks is an infection. These antibodies are specific to the SARS-CoV-2 virus, which means the immune system is primed to protect against future infection.&rdquo

The idea for mRNA vaccines came when Harvard stem cell biologist Derrick Ross started reviewing data from labs in Hungary that talked about creating vaccines to viruses in a totally different fashion, replacing inert viruses with mRNA.

&ldquoWith mRNA technology you get a more robust way of fighting pathogenic viruses than with a conventional flu shot that produces only antibodies,&rdquo Moeller said. &ldquoIt&rsquos a two-pronged attack.&rdquo

The problem is how fragile mRNA is&mdashits life span outside the body is so short that at first no way was found to keep it alive long enough to be injected into the body and taken up into the cells. &ldquoIf you just took naked mRNA and injected it into humans it would break down in 30 seconds,&rdquo Moeller said. &ldquoIt would be toast.&rdquo

Ross got around the problem when he paired with MIT chemical engineer Robert Langer, Moeller said. In 2010 they founded Moderna in Cambridge, Massachusetts. &ldquoThey have 800 scientists,&rdquo Moeller said. &ldquoThe company was founded with the express purpose of creating mRNA vaccines.&rdquo

They discovered that a coating of a nano particle compound &ndash rather like a person wrapping himself in a thermal coat &ndash stabilized the mRNA and made the vaccine possible.

The particle, Moeller said, &ldquois kind of like armor that goes around the mRNA.&rdquo With such armor, kept at incredibly cold temperatures, &ldquoit lives long enough to be taken up by B cells (to make the antibody) and T cells that learn how to fight the virus.&rdquo

Developing and growing an inert virus for a traditional vaccine is &ldquovery cumbersome,&rdquo Moeller said. &ldquoIt takes at least a year to produce.&rdquo

Moderna got a vial of COVID-19 virus from China on January 7, 2020, and &ldquothey did the genome sequence in one day. In two days, they had the technology to design the vaccine,&rdquo Moeller said. &ldquoOnce the virus is sequenced, the speed of production and development is quicker.&rdquo Moderna began its Phase 3 trials and by October its participants had received their second injection, allowing the two months&rsquo required follow-up to be finished by the end of the year.

Moeller admitted that the vaccine has some side effects. &ldquoThe vaccine had two types of reactions,&rdquo he said. &ldquoOne, an allergic reaction of redness at the injection site, soreness in arm, low grade fever. The more serious reaction was related to the PEGylated particle that coats it. It can produce a reactogenic response. What happens then is, you get a flu-like illness with aches pains and fever for up to a week. But it&rsquos limited. Most people will not get that reaction. Less than 1%.&rdquo

As to long-term effects, they are obviously unknown. &ldquoWe have no long-term data,&rdquo Moeller said. &ldquoWe have no data as to how effective they will be on hospitalizations most importantly, how long the immunity will last. Will it be 6 months? 12 months? Two or three years? It may be several years.&rdquo

He emphasized that the mRNA only teaches the cell to fight COVID and does not alter DNA, nor does it carry any type of virus. &ldquoPatients say they&rsquore scared of the vaccine,&rdquo he said. &ldquoWhen this &lsquoinstruction manual&rsquo is put in the body, either the immune cells will pick it up and learn, or nothing will happen.

&ldquoAll that&rsquos being injected is a nucleic acid sequence which codes the immune system into making antibodies against the COVID and teaching the lymphocytes how to fight COVID. It does nothing else at all. That&rsquos why this idea that it could do catastrophic harm is wrong.&rdquo

He said that while there could be a &ldquohypothetical (long term) reaction, it&rsquos not a thing that people are putting on their list of things to worry about. The highest thing they feared was that it wouldn&rsquot work at all.&rdquo

Moeller has a strong faith in the vaccine. &ldquoThis literally can be the light at the end of the tunnel to end this pandemic,&rdquo he said. A vaccine with 60 percent efficacy is considered necessary to develop herd immunity. With mRNA&rsquos 95 percent efficacy &ndash Moeller calls it a home run &ndash &ldquoWe ought to have herd immunity in six month if everybody gets vaccinated.&rdquo

Tomorrow we will conclude this series with a look at COVID treatment in hospitals: what has been learned since it began? And how long do doctors see the rise in patient numbers to continue?


Spike Proteins, COVID-19, and Vaccines

A new study further elucidates the role of spike proteins in COVID-19.

A recent study looks at the effects of the SARS-CoV-2 spike proteins, showing that they can cause some of the harm of COVID-19 by themselves. This is an important advance in our understanding of the disease and hopefully will lead to new therapeutic interventions.

The spike protein is what gives the coronavirus family of viruses their name. The spikes jut out from the surface of the spherical virus, giving it a crown-like halo, hence “corona”. We have also known for a long time that the spike protein is the business end of these viruses, it is what gives the virus its ability to target, latch onto, and enter the cells that it infects. Mutations in the spike protein are also what determine different variants of SARS-CoV-2, and can alter its ability to infect and cause harm.

The new study, however, is the first to directly show that the spike proteins themselves are able to cause harm, and also confirms that COVID-19 is primarily a vascular disease that damages blood vessel walls.

What the researchers did was create a pseudovirus – a protein shell with spike proteins but no viral RNA inside. Therefore these pseudoviruses are unable to actually infect cells or replicate. The point was to isolate as much as possible the effects of the spike proteins themselves. They report:

We administered a pseudovirus expressing S protein (Pseu-Spike) to Syrian hamsters intratracheally. Lung damage was apparent in animals receiving Pseu-Spike, revealed by thickening of the alveolar septa and increased infiltration of mononuclear cells.

They had control animals with a mock virus that did not show this damage. The spike protein binds to the ACE2 receptor on cells, downregulates their function, and causes damage to the endothelium cells that line lung tissue and blood vessels. The damage is apparently caused by effects on the mitochondria (energy producing organelles) in the cells – they change their shape and have reduced function. They then reproduced these effects in vitro using a culture of lung endothelial cells exposed to the spike protein.

These results explain many of the clinical features of COVD-19. While the disease has been largely thought of as a respiratory illness, it is primarily a vascular disease. It affects the lungs, but also affects other organs in the body, and can cause strokes and blood clots. While the vascular effects of coronaviruses have long been known, this study demonstrates a clear mechanism of this injury. Knowing the precise mechanism may lead to treatments to prevent or limit the vascular damage from infection. The next step is to study exactly how downregulating the ACE2 receptor damages the mitochondria.

This study, of course, did not come out of the blue but was built on previous studies showing many of the same findings. It was known, for example, that the ACE2 receptor is important for coronavirus infection, and that it related to endothelium damage. In fact a comment to the FDA by Dr. Whelan nicely summarizes a lot of this research as of December 2020. This research, however, has raised some questions about the safety of the mRNA vaccines that produce spike proteins. To be clear, the safety data on the Pfizer and Moderna mRNA vaccines are now extensive, with hundreds of millions of doses give and months of data, without any significant side effects apparent.

The Pfizer and Moderna vaccines produce the full-length spike protein. Pfizer studied several formulations initially, but found that the full length protein vaccine had fewer side effects and was better tolerated than other vaccine candidates, so that is the one they went with. It is also likely that the full protein contains more epitopes (sites for immune activity) and therefore produces more thorough and longer lasting immunity. The proteins, however, are in a fixed state, they are unable to change their confirmation, which is necessary to bind to cells. So they function differently than spike proteins on infecting virus.

After the Pfizer vaccine full spike proteins are expressed on the vaccinated cells for presentation to the immune system. But the vaccine-induced proteins do not appear to cause any harmful effects. This may be because the vaccine is administered in the muscle, and so muscle cells are the ones taking up the mRNA and making spike proteins. There is a vigorous immune response which neutralizes the spike proteins before they can cause any harm. This is very different from a virus replicating throughout the body.

Unfortunately, the complexity of COVID, mRNA, immunity, and vaccines is such that those who wish to raise fears about the vaccine can exploit partial information. There is a tremendous amount of misinformation about the COVID vaccines, and the mRNA vaccines in particularly, which then has to be constantly rebutted and debunked. That has become almost a full-time job for David Gorski here at SBM . Meanwhile, there is legitimate complexity and concerns that scientists need to carefully sort out, which they are doing, transparently and vigorously.

It’s important not to confuse not knowing everything with knowing nothing. The safety data on the mRNA vaccines is robust. Most vaccine serious side effects occur within six weeks, which is why the FDA wanted at least 6 weeks of safety data before giving the vaccines an EUA. We now have more than 6 months of data, including several months with millions of doses. It is very unlikely there are any surprises still in store with either of the mRNA vaccines. The risk is vanishingly small, while the benefit is clear.


1. Introduction

Of the many COVID-19 vaccines under development, the two vaccines that have shown the most promising results in preventing COVID-19 infection represent a new class of vaccine products: they are composed of messenger ribonucleic acid (mRNA) strands encapsulated in lipid nanoparticles (LNPs). The efficacy of these mRNA vaccines developed by BioNTech/Pfizer and Moderna is about 95% ( Baden et al., 2021 Polack et al., 2020 ) and they were the first mRNA vaccines to receive 𠆎mergency use authorization’ (by FDA) and 𠆌onditional approval’ by EMA. These mRNA COVID-19 vaccines encode the viral Spike (S) glycoprotein of SARS-CoV-2 that includes two proline substitutions (K986P and V987P mutations), in order to stabilize the prefusion conformation of the glycoprotein ( Wrapp et al., 2020 ). Upon intramuscular (IM) administration, the LNP system enables the uptake by host cells and the delivery of mRNA inside the cytosol, where the translation of the mRNA sequence into the S protein occurs in the ribosomes. After post-translation processing by the host cells, the S protein is presented as a membrane-bound antigen in its prefusion conformation at the cellular surface, providing the antigen target for B cells. In addition, part of the temporally produced Spike proteins enter antigen presentation pathways, providing antigen recognition by T cells via MHC presentation of T-cell epitopes ( Verbeke et al., 2021 ). The EMA assessment report formulates the mechanism of action of mRNA vaccines at the injection site as follows: �ministration of LNP-formulated RNA vaccines IM results in transient local inflammation that drives recruitment of neutrophils and antigen presenting cells (APCs) to the site of delivery. Recruited APCs are capable of LNP uptake and protein expression and can subsequently migrate to the local draining lymph nodes where T cell priming occurs ( EMA, 2020a ).’ Because of this inherent innate immune activity, it is not necessary to formulate the mRNA vaccines with additional adjuvants. Interestingly, Pfizer/BioNTech and Moderna specifically use nucleoside-modified mRNA that decrease (rather than increase) the inherent mRNA immunogenicity, underlining the need to properly balance the innate immune activity of mRNA vaccines (see below). The in vivo antigen production post-administration that can be achieved with mRNA vaccines, together with the self-adjuvant properties of mRNA-LNP vaccines, ultimately leads to the efficient generation of neutralizing antibody responses and cellular immunity, decreasing the risk of developing COVID-19 for the vaccine recipients.

mRNA vaccines have several benefits over other types of vaccines. A general advantage of mRNA vaccines is that their development is relatively fast, as mRNA-LNPs are a true platform technology. After identification of the protective protein antigen(s) and sequencing the corresponding gene(s), the mRNA can be made within weeks ( Jackson et al., 2020 ). As the mRNAs encoding different antigens are chemically and physically highly similar, formulation design and manufacturing processes of new mRNA vaccines follow the same steps ( Petsch et al., 2012 ). Compared to replication deficient viral vectors, mRNA vaccines may be more efficacious for COVID-19 prevention. Unlike viral vector-based vaccines, they don’t generate immunity against the carrier. In this regard mRNA vaccines are similar to desoxyribonucleic acid (DNA)-based vaccines. DNA vaccines, however, still have a minute chance of potential genome integration. Moreover, in contrast to mRNA vaccines, DNA vaccines have shown rather low immunogenicity in early clinical trials, possibly because DNA-based vaccines need to gain access to the nucleus to exert their action, complicating efficient delivery. Overall, flexible design, standardized production processes and relatively short-lived cytoplasmic presence make mRNA vaccines very powerful, especially in a pandemic situation with rapidly mutating viruses.

However, one of the greatest challenges encountered when developing mRNA vaccines is their poor stability. Currently, most mRNA vaccines are administered IM, where the mRNA that is taken up by host cells leads to antigen expression ( Hassett et al., 2019 ). Early research on mRNA vaccines has demonstrated that naked mRNA is quickly degraded after administration ( Pardi et al., 2015 , Wayment-Steele et al., 2020 ). Consequently, over the last few years efforts were made to improve the in vivo stability of mRNA after administration. This led to ways to optimize the mRNA structure by slowing down its degradation (see under section ‘mRNA stability’). Another successful and currently widely used approach is to encapsulate and protect the mRNA in LNPs ( Pardi et al., 2015 ). This reduces premature mRNA degradation after administration and enhances delivery to the cytosol of antigen-presenting cells ( Liang et al., 2017 , Lindsay et al., 2019 ).

Although progress has been made to enhance the stability in vivo and efficacy of mRNA-LNP vaccines, much less attention has been paid to their stability during storage ( Crommelin et al., 2021 ). In order to effectively distribute a vaccine worldwide, it should have a sufficiently long shelf life, preferably at refrigerator temperatures (2𠄸 ଌ) or above. Currently, hardly any data is available in the public domain on what happens when mRNA-LNP formulations are stored for long periods of time. Moreover, it is unclear to what extent entrapping mRNA within LNPs influences the storage stability of the mRNA vaccine. Additionally, very little is known about the structure and morphology of LNPs formulated with mRNA, the chemical stability of the LNP components and the colloidal stability of the mRNA-LNP system. What is known now is that in order to store the current mRNA COVID-19 vaccines for longer periods of time, they have to be frozen. The current mRNA COVID-19 vaccines of Moderna and BioNTech/Pfizer have to be kept between � and � ଌ and between � and � ଌ, respectively ( EMA, 2020a , EMA, 2021 ). To date, the degradation processes and the reasons why storage temperature requirements differ, are not fully understood.

The requirement of storing the mRNA-LNPs in a frozen state hampers vaccine distribution. Especially, the very low temperature of � to � ଌ is a major obstacle when it comes to vaccine transport, storage and distribution among end-users worldwide. Most other vaccines can be stored at 2𠄸 ଌ. Clearly, there is a need and opportunity to find ways of stabilizing mRNA-LNP vaccines to allow non-frozen storage. This review provides an overview of approaches to make mRNA vaccines more stable, so that they can be stored longer at less extreme temperatures. To explore the topic, the characteristics of mRNA-LNP vaccines and their influence on storage stability are discussed. This information is used to identify the reasons for mRNA vaccine instability and to explore technological options for stability improvement.


4. Immune responses and protection induced by COVID-19 mRNA vaccines

The COVID-19 mRNA vaccines are primarily focused on triggering B cells to promote the induction of neutralizing antibodies, but there are also good reasons to believe that CD8 + T cell and CD4 + T cell responses may contribute to the protection against SARS-CoV-2 [ 66 ]. Memory T cells, particularly those residing at the upper airways might limit disease severity and shorten the duration of disease by rapidly eliminating infected cells and coordinating the production of antibodies [ 67 ]. In COVID-19 patients, a coordinated adaptive immunity of CD4 + T cells, CD8 + T cells, and antibody responses was correlated to milder disease, whereas an uncoordinated response frequently failed to control disease [ 68 ]. Moreover, previous experience with the closely related SARS-CoV-1, showed that CD8 + and CD4 + memory T cells were detectable as late as 17 years post-infection, while neutralizing antibody titers had waned substantially by 1 year after infection [ 69 , 70 ]. Although these reports clearly attribute beneficial roles to T cells in controlling COVID-19 and durability of immunity, T cells, on their own, will probably not be capable to prevent viral entry by providing sterilizing immunity against SARS-COV-2.

As for humoral immunity, two vaccine doses of CVnCoV (12 μg mRNA dose) induced SARS-CoV-2 neutralizing antibody titers in all participants at levels that were comparable to those found in individuals who had recovered from natural infection [ 57 ]. In comparison, the nucleoside-modified mRNA vaccines BNT162b2 (30 μg mRNA dose) and mRNA-1273 (100 μg mRNA dose) generally surpassed the titers from convalescent COVID-19 patient samples, even in the elderly trial group, hinting towards potential stronger induction of humoral immunity to the unmodified mRNA vaccine CVnCoV [ 49 , 53 ]. Since the type I IFN activity can be better controlled with 1mΨ-modified mRNA, resulting in higher maximal tolerable doses of the 1mΨ-modified mRNA vaccines, they might achieve a more durable protein expression and thus prolonged antigen availability. This is a particularly favorable feature to enhance germinal center (GC) responses. In GCs, B cells undergo affinity maturation and isotype switching. After rounds of clonal expansion, this gives rise to high affinity B cells and their differentiation into plasma cells and memory B cells, which eventually determines the quality and durability of the antibody response.

Moreover, several studies have shown that i.m. delivery of 1mΨ-modified mRNA vaccines results in the rapid and potent induction of follicular T helper cells (Tfh) [ 71 , 72 ]. This specialized T cell phenotype is essential for the proper regulation of GCs [ 73 ]. Indeed, Pardi and colleagues recently demonstrated that a single immunization of mice with 1mΨ-modified mRNA LNP vaccines could elicit potent S-specific GC B cells and Tfh cells, in which their absolute numbers correlated with the levels of neutralizing antibodies [ 74 ]. In humans, both BNT162b2 and mRNA-1273 elicited S-specific CD4 + T cell responses directed against the S1 (including RBD) and S2 regions of the S glycoprotein, which again highlights the benefit of delivering mRNA encoding the full-length S protein [ 50 , 53 ]. The magnitude of CD4 + T cell responses correlated with the levels of S-binding IgG antibodies, underlining their supporting role in humoral immunity, Moreover, the majority of the activated CD4 + T cells displayed a Th1 skewed profile (i.e. cells producing IFN-ɣ, TNF-α, and IL-2), which is believed to be very important to potentially avoid vaccine-associated enhanced respiratory disease, in particular the risk for antibody-dependent enhancement and/or lung eosinophilic immunopathology upon SARS-CoV-2 infection [ 75 ].

With regards to inducing CD8 + T cell responses, study results indicate that BNT162b2 outperforms mRNA-1273. Most of the study participants vaccinated with BNT162b2 mounted significant S-specific CD8 + T cell responses (91.9%) [ 50 ], as compared to low or undetectable levels in the clinical evaluation of mRNA-1273 [ 53 ]. From the preclinical evidence of CVnCoV in mice, it can be appreciated that high numbers of S-specific CD8 + T cells were detected after two rounds of vaccination (up to 10% of total splenic CD8 + T cells) [ 56 ]. However, this capacity of CVnCoV to elicit robust CD8 + T cell responses could not yet be confirmed in humans, nor were any details on T cell activation reported in the first clinical data of the phase 1 trial of this mRNA vaccine [ 57 ].

The interim analysis report on the ongoing phase 3 trial of BNT162b2 showed that a two dose vaccine regimen was very effective in preventing COVID-19 disease (up to 95% efficacy) [ 51 ]. The vaccine efficacy of mRNA-1273 is in line with the outcome of BNT162b2, conferring 94.1% protection against symptomatic COVID-19 disease [ 54 ]. Moreover, real-world data from Israel's immunization program with BNT162b2 demonstrate that two weeks after the second dose vaccine effectiveness was estimated at 97% in preventing symptomatic and severe COVID-19 disease, while the vaccine was 94% effective against asymptomatic SARS-CoV-2 infections [ 76 ]. Supported by evidence obtained in viral challenge experiments in non-human primates that both vaccines produced rapid viral control in the upper and lower airways, we can hope that the mRNA vaccines are also capable to avoid viral transmission and thus curtailing the pandemic spread. [ 48 , 52 ].

Whether these mRNA vaccines are also effective against new SARS-CoV-2 variants, including the emerging U.K variant (B1.1.7) and the South African variant (B.1.351), was recently assessed by measuring neutralizing antibody activities against pseudoviruses bearing the mutated B.1.1.7 or B1.351 spike protein [ [77] , [78] , [79] ]. The neutralization activity of sera collected from both mRNA-1273 and BNT162b2 vaccinated individuals was largely preserved against the B.1.1.7 variant relative to prior variants. In contrast, in a study by Moderna a 6.4-fold reduction in neutralization titers was detected against a pseudovirus with a full set of B.1.351 mutations, but remained above levels that are expected to be protective and sera of all individuals were capable to obtain full neutralization [ 78 ]. Moreover, in response to this emerging South Africa coronavirus variant, Moderna already announced that they are working on an adapted booster vaccine candidate (mRNA-1273.351) [ 80 ].

How, and for how long the different vaccine-induced immune responses will contribute to the protection will need to be determined in long-term follow up studies. Moderna already reported that neutralizing antibodies continued to be detected in all the participants at 3 months post-vaccination [ 81 ]. Future studies should also try to investigate the generation of long-lived memory B cells and T cells, as it can be expected that neutralizing antibodies will wane over time, while these memory cells may be long-lived and provide rapid responses upon infection.


RELATED STORY

&ldquoIt is estimated that there may be tenfold more asymptomatic carriers of the disease, which means that there could be over seven-and-a-half million carriers worldwide,&rdquo said Subramani. &ldquoThis is a disease that is spreading very rapidly across the globe, so these faculty are here to share their knowledge regarding the biology of the virus and why this pandemic has brought the world to its knees.&rdquo

Emily Troemel, a professor who studies host-pathogen interactions in the Section of Cell and Developmental Biology, kicked off the discussion by describing basic biological aspects of coronaviruses, including how health workers test for the presence of SARS-CoV-2 infection and facets scientists have learned about the virus&rsquo genome.

Coronaviruses, as Troemel noted, feature RNA-based genomes, unlike most of life on the planet, which feature DNA genomes. RNA genomes in coronaviruses are positive-sense, which are similar to the cell&rsquos own messenger RNA and allows these viruses to immediately hijack the protein synthesis machinery of host cells. This feature enables these viruses to quickly and effectively take over host cells and rapidly expand.

&ldquoKnowing that it has RNA in its genome helps us understand how we test for the presence of coronavirus,&rdquo said Troemel. &ldquoIn addition, we are able to look at changes in the sequence in the viral genome and that&rsquos enabling us to track the spread of this virus around the globe&hellip. We can learn about how the biology of the virus is changing and how it may be altering the way it interacts with host cells, and also potentially different ways that we could treat it. It&rsquos part of an amazing open science effort with an unprecedented level of information acquisition and information sharing among researchers.&rdquo

Matt Daugherty, an assistant professor in the Section of Molecular Biology, studies the evolutionary arms race that pits the immune systems of hosts on one hand and pathogens on the other. He covered aspects such as how SARS-CoV-2 and other viruses enter the human population and become pandemics how SARS-CoV-2 relates to past and present epidemic viruses in the human population and, based on what scientists have learned from other viruses, what we can expect in terms of long-term immunity and co-existence with SARS-CoV-2.

&ldquoWe as a species are always being exposed to viruses,&rdquo Daugherty noted.

Since SARS-CoV-2 is so new, there are many key unknowns related to human immune defenses against it, Daugherty said. Even with coronaviruses that cause common colds, it&rsquos unclear whether humans develop long-term immunity to these viruses or need to continually develop new immunities.

&ldquoOne thing I take comfort in with all of these other viruses is knowing that we aren&rsquot constantly dealing with influenza pandemics and other pandemic viruses, and that&rsquos because of the largely effective role of our immune system in dealing with these viruses once the immune system has been prepared,&rdquo said Daugherty.

For a virus that originated in an animal species to successfully infect humans, it needs to adapt to a range of genetic differences between the original host species and humans. But effective vaccines can ultimately thwart such pathogens.

&ldquoWe have really good ways of making effective vaccines, and the hope is that this will hold for SARS-CoV-2 as well,&rdquo said Daugherty. &ldquoI take some comfort in knowing that these types of pandemics do pass and we will get through this.&rdquo

Justin Meyer, an assistant professor in the Section of Ecology, Behavior and Evolution, discussed concepts related to science and society&rsquos ability to predict future pandemics. These include variables that contribute to the spread of pathogens the increased likelihood of future pandemics and predictions for where the next pandemic is likely to occur.

Factors that boost the risk of pandemics include human exposure to pathogens through meat consumption and contact with wild animals, increased human encroachment in wild areas and the exotic animal trade. Increased urbanization&mdashmore people living in close proximity means more opportunities for viruses to spread&mdashand the rising consequences of climate change, also increase pandemic risks.

&ldquoWe&rsquore augmenting the temperature of the earth and environments in a way that we&rsquore making ourselves more susceptible to diseases,&rdquo said Meyer. &ldquoWhen we warm the earth, we create more habitats for mosquitoes that carry vectors like malaria by increasing their range. They can spread to new human populations. By increasing temperatures, we&rsquore increasing flooding and there are many pathogens that are waterborne, such as cholera, which we will be exposing more and more people to.&rdquo

During the roundtable discussion, Subramani prompted the scientists with a handful of questions, including: Since many coronaviruses are relatively harmless, what makes SARS-CoV-2 so damaging to the lungs? What is the appropriate vaccine target for SARS-CoV-2 and in what time frame&mdashfrom validation to FDA approval&mdashis a vaccine likely? Can we look to drug targets where vaccines have been developed for related viruses and would that timeline be the same? Is there any evidence that SARS-CoV-2 has a mutation rate that is extraordinarily high?


The Elm

Messenger RNA (mRNA) technology creates immunity in a different way than traditional vaccines and is one reason the coronavirus vaccine was developed in less than a year.

As COVID-19 vaccines begin to be distributed, many are wondering exactly how the vaccine works and if it is safe.

The COVID vaccines that are currently approved are from Pfizer-BioNTech and Moderna, Inc., who utilized Messenger RNA (mRNA) technology to create their vaccines.

This breakthrough technology, which creates immunity in a different way than traditional vaccines, is one reason the COVID vaccine testing and development took less than a year.

How Vaccines Work

When a person is infected with a germ, whether a virus or bacteria, the immune system creates special proteins, called antibodies, that help protect against future infections from that germ. The next time your immune system sees that germ, it “remembers” and uses the antibodies to fight against the infection. Some antibodies only last a few months, while others can protect you for a lifetime.

Vaccines create antibodies that allow your body to protect itself from future infections without actually getting sick.

Previously developed vaccines contain very small amounts of viruses or bacteria that are dead or greatly weakened. They trick the immune system into believing that the body is being infected.

The COVID vaccine is no different in that it creates antibodies, but it uses a different set of tricks than traditional vaccines to create coronavirus immunity.

How mRNA Vaccines Work

Messenger RNA is a piece of genetic material that cells use as “instructions” to create certain proteins in the body. It is like a bit of computer code.

When it’s not inside a cell, mRNA needs protection to keep it from disintegrating. This is why the vaccines require cold temperature storage. To keep the mRNA from disintegrating when it enters the body, the COVID-19 vaccines use fat bubbles to shuttle the mRNA to certain cells.

The mRNA instructs these cells to create “spike proteins.” These proteins simulate part of the SARS-CoV-2 (novel coronavirus) cell structure and trick the body into believing it’s infected with the virus.

In the case of the mRNA vaccines, your body is never exposed to the germ but is still able to produce an effective immune response.

What’s in the COVID Vaccines?

Like all other vaccines approved by the Food and Drug Administration, COVID vaccines do not contain toxic or harmful ingredients. This is another common vaccine myth.

One of the benefits of using the current COVID vaccines is that they avoid some of the issues some people may have with certain vaccines.

The vaccines aren’t made using egg proteins, so unlike some forms of the flu vaccine, people who have an egg allergy can take the vaccine.

Additionally, human fetal cells aren’t used during the vaccine development process. This makes the COVID vaccines a suitable option for individuals who object to this practice.

How Long Will Immunity Last?

Scientists are still studying exactly how long the vaccine’s protection will last. The volunteers who were part of the COVID-19 vaccine studies agreed to be followed for two years to help researchers determine exactly how long immunity lasts.

Both the Pfizer and Moderna vaccines require two doses to achieve immunity. This ensures that your immune system will build up enough antibodies to remember and protect against future COVID infections. Learn more important facts about the COVID vaccine.

Can You Get COVID from the Vaccine?

Vaccines that contain either dead germs or small pieces of germ protein can’t make you sick. This is a common vaccine myth. Some vaccines have some mild side effects, such as fatigue or a low-grade fever. This is a result of the body's immune system response, not the virus.

Will an mRNA Vaccine Affect My DNA?

Because mRNA “instructs” cells to perform certain actions, some people have expressed concerns about the vaccine affecting their DNA. This is not true. mRNA vaccines will never interact with the body’s DNA. In fact, once the cell has finished using the mRNA, the cells break it down and eliminate it from the body.


The Science Behind The Historic mRNA Vaccine

Sandra Lindsay, left, a nurse at Long Island Jewish Medical Center, is inoculated with the Pfizer-BioNTech COVID-19 vaccine by Dr. Michelle Chester, Monday, Dec. 14, 2020. Mark Lennihan/AP hide caption

Sandra Lindsay, left, a nurse at Long Island Jewish Medical Center, is inoculated with the Pfizer-BioNTech COVID-19 vaccine by Dr. Michelle Chester, Monday, Dec. 14, 2020.

As we surpassed 300,000 coronavirus deaths in the U.S., there was one small bright spot just days earlier: the Pfizer-BioNTech vaccine was granted emergency use authorization by the FDA. It is the first widely-available vaccine to use something called mRNA technology.

How it works

After the vaccine is injected into a person's arm, the muscle cells will essentially swallow the mRNA, bringing it into the cell. From there, our body uses mRNA to make a coronavirus protein that your immune system can recognize and respond to. After getting the vaccine, if you are exposed to the real coronavirus, antibodies can recognize that protein, grab on to it, and keep the virus from getting into our cells.

How it was developed

As epidemiologist Rene Najera explains, while this is the first time a vaccine with this technology has been authorized, the technology is not new. The speed was also enabled by the global scientific community: pretty much as soon as the genetic sequence for the virus was released in January of this year, scientists across the globe began working on vaccines. It also helps that this particular vaccine is easier for scientists to make in the lab compared to others like the flu vaccine.

Additional resources to learn more:

This episode was produced by Rebecca Ramirez, fact-checked by Ariela Zebede and edited by Viet Le and Gisele Grayson. Alex Drewenskus was the audio engineer this episode.


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Our fact check work is supported in part by a grant from Facebook.