Some key questions about mRNA vaccines

preface

mRNA-based therapies represent a relatively novel and highly effective class
of drugs.
During the COVID-19 pandemic, mRNA vaccines have evolved at breakneck speed and have become one of
the hot areas of research today.
mRNA vaccines have shown excellent efficacy in protection against SARS-CoV-2 and have shown potential efficacy
in treating different types of malignancies and other infectious diseases.

However, there are still many doubts about the safety of mRNA vaccines, and at present, mRNA vaccines have only been approved for SARS-CoV-2 prevention, and their efficacy in other aspects needs further research
.
There are many problems that need to be solved, and let's explore some of the key issues
that future mRNA vaccines may face.

Duration of antigen reaction

After vaccination, antigens are taken up by antigen-presenting cells and transported to lymph nodes, where interactions between B cells, antigen-presenting cells, and follicular helper T cells (Tfh) promote the formation of
germinal centers.
Within germinal centers, B cells then proliferate, differentiate, and mutate their antibody genes to produce high-affinity neutralizing antibodies
against the attacking antigen.
Germinal central responses and Tfh cell induction are essential for a long-lasting antibody response, which will protect patients for months or years
.

To enhance this first step in the immune response process, some delivery systems target antigen-presenting cells to translate mRNA
.
Several promising strategies for actively targeting antigen-presenting cells include binding monoclonal antibodies to the LNP surface and modifying the LNP surface
with dendritic cell-specific ligands.
Alternatively, modulating the physical properties of LNPs, such as surface charge, has been used to improve cancer vaccine efficacy
.

In addition, altering vaccine pharmacokinetics by prolonging the translation of antigen mRNA has become an exciting tool
to enhance antibody responses.
Sustained antigen availability during germinal center reactions has been shown to increase antibody production by approximately 10-fold
.
A study in mice showed that nucleoside-modified mRNA had longer cycling times and induced stronger Tfh cell and germinal center B cell responses
compared to unmodified mRNA.

In clinical trials, two doses of mRNA-1273 also triggered a durable antibody response
within 6 months.
Although antibody titers decreased slightly during the study period, high neutralization capacity
remained in all age groups.
These results are promising, however, the duration of the antibody response is a complex phenomenon that varies from antigen to antigen and requires longer-term data to fully understand
.

Mutations against viruses

Mutations in viral genomes are common
during replication.
Although most mutations have little or no effect on the function of the virus, some can enhance immune evasion and hinder vaccine development
.
For example, for more than 30 years, rapid mutations in HIV have hindered the development of effective vaccines, while mutations in influenza viruses require annual modifications in vaccine formulations to target dominant strains
.

The emerging SARS-CoV-2 variant has also raised concerns
about the cross-variant efficacy of mRNA vaccines.
B.
1.
351 and P.
1 variants have glutamate (E) to lysine (K) mutations at position 484 (E484K) of the spike protein receptor binding domain, which promotes immune evasion
。 Fortunately, the FDA-approved mRNA vaccines BNT162b2 and mRNA-1273 produced cross-neutralizing antibodies against B.
1.
351 and P.
1, as well as other variants, suggesting that they can provide protection
against them.
However, the cross-neutralization effect has been significantly reduced
compared to the first virus.
In addition, in CureVac's Phase IIb/III trial of CVnCoV candidates, 57% of the 124 COVID-19 cases sequenced were mutants, including the B.
1.
351 and P.
1 variants
.

If these variants gradually become the dominant variant over time, mutant-specific mRNA enhancers
may be required.
Currently, Moderna is evaluating the original mRNA-1273 vaccine and the latest version of the vaccine as a third booster: mRNA-1273.
351, which encodes the spike protein from the B.
1.
351 variant, and mRNA-1273.
211, a 1:1 combination of mRNA-1273 and mRNA-1273.
351
.

In the long run, pan-coronavirus vaccines that provide protection against SARS-CoV-2 and future coronavirus outbreaks will be more beneficial
.
As with HIV and influenza, new structural insights are expected to facilitate the discovery of conserved sites of coronavirus, accelerating antigen discovery and vaccine design
.

security

Overall, mRNA vaccines have a good safety profile, with only mild or moderate adverse events
occurring in clinical trials.
However, there are individual events that call for further optimization of mRNA antigen and vehicle components
.
For example, CureVac's protamine-based rabies drug candidate CV7201 caused serious adverse events in 78% of participants, prompting CureVac to adopt LNPs as the preferred dosing platform
for its subsequent rabies candidate, CV7202.

As with most drugs, adverse effects of mRNA vaccines tend to increase
with increasing dose.
For example, in the Phase I trial of CV7202, a 5 μg dose had unacceptable toxicity, while 1 μg was the highest dose
that was well tolerated.
In addition, in the first phase of the Moderna H10N8 influenza vaccine trial, serious adverse events occurred in patients at a 400 ug dose, therefore, the trial continued
at a dose of 100 μg.

When using Pfizer–BioNTech and Moderna's COVID-19 vaccines, allergic reactions were observed in about 4.
7 and 2.
5 per million vaccinated people, respectively, which is approximately 2-4 times
higher than conventional vaccination.
One theory is that allergic reactions are attributed to pre-existing antibodies
in the population against pegylated lipids in LNPs.
These antibodies are thought to respond to PEG in many consumer products, such as toothpaste, shampoos, and laxatives.

Anti-PEG antibodies have been reported in 40% of the population, which may increase the risk of allergic reactions in some individuals and hinder the efficacy
of the vaccine.
Currently, the CDC recommends that mRNA vaccines
should not be used for individuals with a history of allergies to any component of the Pfizer–BioNTech or Moderna vaccines.
Clearly, we need to better understand how mRNA vaccine formulations cause allergic reactions so that formulations can be redesigned to improve safety
.

Vaccination of specific populations

Most vaccines, whether conventional or mRNA, are developed
for children or healthy adults.
However, some populations may benefit from alternative vaccination strategies or respond differently
to vaccination due to differences in immune systems.

Maternal/neonatal vaccinations

The dynamic nature of the immune system during pregnancy increases a person's susceptibility to infectious diseases, which can have catastrophic effects on
maternal health and fetal development.

To address these challenges, maternal vaccination has become a tool to
improve maternal health and reduce neonatal morbidity.
By binding to the neonatal Fc receptor, maternal IgG antibodies easily cross the placenta and enter the fetal circulation, protecting the fetus from pathogens
.
In several studies, maternal inoculation of mRNA-loaded LNPs prevented fetal Zika virus transmission in pregnant mice and protected newborn mice from infection by herpesvirus and streptococcus
.

Although vertically metastasized maternal antibodies can prevent infection in newborns, they can also hinder the effect of vaccination on infants later in life, the mechanism of which is unclear
.
Prolonged antigen availability may promote a stronger germinal center response, resulting in a robust infantile immune response
in the presence of maternal antibodies.

The mRNA vaccine against SARS-CoV-2 has also been shown to be immunogenic in pregnant and lactating populations, and neutralizing antibodies
have been detected in cord blood and human milk.
Preliminary data suggest that mRNA-1273 and BNT162b2 cause similar adverse events in pregnant and non-pregnant people, and that the vaccine does not increase the incidence
of neonatal death or congenital anomalies.
However, further longitudinal studies are needed to assess the impact of
mRNA vaccines on maternal and newborn health.

senior citizen

This group is in dire need of an effective vaccine, as many infectious diseases affect the elderly
.
For example, 70 to 90 percent of flu-related deaths occur in patients over the age of 65, while COVID-19 is 62 times
more likely to die in patients older than younger patients.

It is more difficult for older people to vaccinate because aging adversely
affects both innate and adaptive responses of the immune system.
Reduced expression of toll-like receptors prevents monocytes and macrophages from secreting cytokines and chemokines and limits crosstalk
with the adaptive immune system.
The adaptive immune response during infection is often inadequate
due to impaired cytokine signaling and physiological and cellular changes.
These changes include thymic degeneration, decreased naïve B cells and T cells, reduced diversity of T cell receptors, higher susceptibility to T cell apoptosis, and decreased
expression of key receptors such as CD28 on cytotoxic CD8+ T cells.

Fortunately, there is growing evidence that mRNA vaccines may have a strong potency
in all age groups.
For example, in a phase III trial, Pfizer–BioNTech's vaccine candidate BNT162b2 was more than 93%
effective across all treatment groups.
The Moderna vaccine candidate, mRNA-1273, was also highly effective, showing 86.
4% efficacy in volunteers aged ≥ 65 years, compared to 95.
6%
in volunteers aged 18-65.

The design of delivery vehicles is important
to improve vaccine efficacy in older people.
mRNA vectors can act as inflammatory adjuvants to amplify vaccine responses
by enhancing the recruitment of antigen-presenting cells to the injection site.
In a preclinical study, CureVac's RNAVAC activated TLR7 and generated a durable immune response
against deadly influenza in mice.
Novartis' emulsion MF59 has been used as an mRNA delivery vehicle and can also be used as an adjuvant
.
MF59 enhances the immunogenicity of influenza vaccines and has been approved for use in older adults
.

Access to vaccines

Access to vaccines is the biggest challenge to achieving widespread protection against infectious diseases, especially in low-income countries
.
Refrigeration requirements for currently approved SARS-CoV-2 mRNA vaccines further limit access
to vaccines.
Portable and reusable Arktek freezers can enable rapid deployment
of millions of doses of vaccines during pandemics.

However, billions of people need to be vaccinated against the COVID-19 virus, which requires heat-resistant vaccines
.
Currently, there are two SARS-CoV-2 vaccine candidates that are heat-tolerant at room temperature, and if these heat-resistant vaccine candidates can show good results in clinical trials, they may simplify global access
to mRNA vaccines in the near future.

Vaccine acceptance

Vaccines are only effective after vaccination, and the data supporting their safety and efficacy is abundant, and vaccines have eradicated several infectious diseases in parts of the world, saving countless lives
.
However, public distrust has increased due to misinformation and anti-vaccine campaigns, threatening the maintenance of herd immunity and putting our most vulnerable populations at risk
.

Declining vaccination coverage could lead to the re-emergence
of life-threatening diseases.
For example, measles, which was eradicated from the United States in 2000, infected more than 1,200 people in 2019 due to poor vaccine adherence in multiple communities
.
For COVID-19, the current acceptance of 56–75% in the US may not be sufficient to achieve at least 80–90% coverage, a threshold considered necessary
for herd immunity to SARS-CoV-2.

While much of the burden of improving vaccine coverage falls on governments and public health officials, the scientific community can also help
by improving the efficacy and safety of mRNA vaccines.
Increased efficacy will reduce the acceptance required for herd immunity, and improved safety will discourage media coverage of adverse events, thereby reducing fear of vaccination
.

brief summary

Decades of advances in mRNA design and nucleic acid delivery technology, coupled with the discovery of neoantigen targets, have made mRNA vaccines an extraordinary tool
against emerging and existing infectious diseases.
Two mRNA vaccines against SARS-CoV-2, developed at a revolutionary pace and offering superior protection rates, are expected to end the COVID-19 pandemic
.

In addition, these vaccines elevate LNP and RNA therapeutics from niche products to preventive treatments
that have been successfully implemented in large populations.
The result is a wealth of safety and efficacy data, as well as successful regulatory approvals
.
We can be optimistic that mRNA therapy may change the way modern medicine is used for vaccination, cancer immunotherapy, and protein replacement therapy
.

References:

1.
mRNA vaccines for infectious diseases: principles, delivery and clinical translation.
Nat RevDrug Discov.
 2021 Aug 25 : 1–22.

： ，
。   ， ，