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What are unresolved issues on mRNA vaccines?
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What are unresolved issues on mRNA vaccines?
mRNA-based therapeutics represent a relatively novel and highly effective class of drugs.
During the COVID-19 pandemic, mRNA vaccines have been rapidly developed and become one of the hottest areas of current research.
mRNA vaccines have shown remarkable efficacy in protection against SARS-CoV-2, and have also shown potential efficacy in the treatment of different types of malignancies and other infectious diseases.
However, there are still many doubts about the safety of mRNA vaccines. At present, mRNA vaccines are only approved for the prevention of SARS-CoV-2, and their efficacy in other aspects remains to be further studied.
Many problems need to be solved. Let’s discuss some key problems that mRNA vaccines may face in the future.
Antigen Response Duration
Following vaccination, antigens are taken up by antigen-presenting cells and transported to lymph nodes, where interactions between B cells, antigen-presenting cells, and T follicular helper cells ( Tfh) promote germinal center formation .
Within the germinal center, B cells then proliferate, differentiate, and mutate their antibody genes to produce high-affinity neutralizing antibodies against aggressive antigens.
Germinal center responses and Tfh cell induction are critical for a durable antibody response that 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 to actively target antigen-presenting cells include binding monoclonal antibodies to the LNP surface and modifying the LNP surface with dendritic cell-specific ligands.
Alternatively, modulating physical properties of LNPs, such as surface charge, has been used to improve cancer vaccine efficacy.
Furthermore, altering vaccine pharmacokinetics by prolonging the translation of antigen mRNA has emerged as an exciting tool for enhancing antibody responses.
Sustained antigen availability during germinal center reactions has been shown to increase antibody production approximately 10-fold.
A study in mice showed that nucleoside-modified mRNAs circulated longer and induced stronger Tfh cell and germinal center B-cell responses compared with unmodified mRNA.
In clinical trials, two doses of mRNA-1273 also elicited durable antibody responses over six months. Although antibody titers decreased slightly during the study period, all age groups maintained high neutralizing capacity.
These results are promising, however, the duration of antibody responses is a complex phenomenon that will vary for different antigens and longer-term data are needed to be fully understood.
Mutations against viruses
Mutations in the viral genome are common during replication. Although most mutations have little or no effect on the function of the virus, some mutations can enhance immune evasion, hampering vaccine development.
For example, rapid mutations in HIV have hindered the development of effective vaccines for more than 30 years, while mutations in influenza viruses have required annual revisions of vaccine formulations to target dominant strains.
Emerging SARS-CoV-2 variants have also raised concerns about the efficacy of mRNA vaccine crossover variants.
The B.1.351 and P.1 variants harbor a glutamic acid ( E ) to lysine ( K ) mutation 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 generated cross-neutralizing antibodies against B.1.351 and P.1, as well as other variants, suggesting that they may confer protection against them.
However, the cross-neutralization effect has been significantly reduced compared to the first viruses.
Furthermore, in CureVac’s phase IIb/III trial of its candidate CVnCoV, 57% of the 124 COVID-19 cases sequenced were mutants, including the B.1.351 and P.1 variants.
Variant-specific mRNA enhancers may be required if these variant strains become dominant over time. Moderna is currently evaluating the original mRNA-1273 vaccine and the latest version as a third-dose booster: mRNA-1273.351, which encodes the spike protein from the B.1.351 variant, and mRNA-1273.211, an mRNA-1273 A 1:1 mixed vaccine with mRNA-1273.351.
Pan-coronavirus vaccines that provide protection against SARS-CoV-2 and future coronavirus outbreaks will be more beneficial in the long run. As with HIV and influenza, new structural insights are expected to facilitate the discovery of conserved sites in coronaviruses, accelerating antigen discovery and vaccine design.
Overall, mRNA vaccines have a good safety profile, with only mild or moderate adverse events occurring in clinical trials.
However, there were also individual events that required further optimization of mRNA antigen and delivery vehicle components.
For example, CureVac’s protamine-based rabies candidate, CV7201, caused serious adverse events in 78% of participants, prompting CureVac to adopt LNPs as the preferred delivery platform for its follow-on rabies candidate, CV7202.
As with most drugs, adverse effects of mRNA vaccines tend to increase with dose. For example, in a phase 1 trial of CV7202, the 5 μg dose had unacceptable toxicity, while 1 μg was the highest dose that was well tolerated.
In addition, in the phase 1 trial of Moderna H10N8 influenza vaccine, serious adverse events occurred in patients at the 400ug dose, therefore, the trial continued at the 100μg dose.
When using the COVID-19 vaccines from Pfizer–BioNTech and Moderna, allergic reactions were observed in approximately 4.7 and 2.5 per million recipients, respectively, which is approximately 2-4 times higher than conventional vaccination.
One theory is that the anaphylaxis is due to pre-existing antibodies in the population against the PEGylated lipids in LNP. These antibodies are thought to react to PEG in many consumer products such as toothpaste, shampoo 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 in individuals with a history of allergy to any component of the Pfizer–BioNTech or Moderna vaccines.
Clearly, we need a better understanding of how mRNA vaccine formulations elicit allergic responses so that formulations can be redesigned to improve safety.
Vaccination for Specific Populations
Most vaccines, whether traditional or mRNA, are developed for children or healthy adults. However, due to differences in the immune system, some populations may benefit from alternative vaccination strategies or respond differently to vaccination.
The dynamic nature of the immune system during pregnancy increases a person’s susceptibility to infectious diseases that can have catastrophic effects on maternal health and fetal development.
To address these challenges, maternal vaccination has emerged as a tool to improve maternal health and reduce neonatal morbidity. Maternal IgG antibodies can easily cross the placenta and enter the fetal circulation by binding to neonatal Fc receptors to protect the fetus from pathogens. In several studies, maternal vaccination with mRNA-loaded LNPs prevented fetal Zika virus transmission in pregnant mice and protected neonatal mice from herpesvirus and streptococcal infection.
Although vertically transferred maternal antibodies protect against infection in newborns, they also impede the effect of vaccination on infants later in life, by mechanisms that are unclear. Prolonged antigen availability may promote a stronger germinal center response, resulting in a robust infant immune response in the presence of maternal antibodies.
An mRNA vaccine against SARS-CoV-2 has also been shown to be immunogenic in pregnant and lactating populations, and neutralizing antibodies were detected in cord blood and human milk. Preliminary data suggest that mRNA-1273 and BNT162b2 elicited similar adverse events in pregnant and non-pregnant populations, and that the vaccines did not increase the incidence of neonatal deaths or congenital anomalies. However, further longitudinal studies are needed to assess the effects of mRNA vaccines on maternal and neonatal health.
Effective vaccines are urgently needed for this group because many infectious diseases affect older adults. For example, 70 to 90 percent of influenza-related mortality occurs in patients older than 65 years, and the death rate from COVID-19 is 62 times higher in patients older than 65 years than in younger patients.
Older adults are more difficult to vaccinate because aging adversely affects both the 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. Adaptive immune responses during infection are often inadequate due to impaired cytokine signaling and physiological and cellular changes.
These changes include thymus involution, reduction of naive B and T cells, decreased diversity of T cell receptors, higher susceptibility to T cell apoptosis, and reduced expression of key receptors such as CD28 on cytotoxic CD8+ T cells.
Fortunately, mounting evidence suggests that mRNA vaccines may be robustly effective in all age groups. For example, in a Phase III trial, Pfizer–BioNTech’s vaccine candidate BNT162b2 was more than 93% effective in all treatment groups. Moderna’s vaccine candidate mRNA-1273 was also very potent, showing 86.4% efficacy in volunteers ≥65 years old, compared to 95.6% efficacy in volunteers 18-65 years old.
Delivery vehicle design is important to improve vaccine efficacy in older adults. 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 produced 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 the elderly.
Access to vaccines
Access to vaccines is the greatest challenge to achieving widespread prevention of infectious diseases, especially in low-income countries.
The refrigeration requirements of currently approved SARS-CoV-2 mRNA vaccines further limit vaccine access.
Portable and reusable Arktek freezers enable rapid deployment of millions of doses of vaccines during epidemics.
However, the COVID-19 virus needs to vaccinate billions of people, which requires heat-resistant vaccines.
There are currently two SARS-CoV-2 vaccine candidates that are thermostable at room temperature, and if these thermostable candidates can show promising results in clinical trials, they may simplify global access to mRNA vaccines in the near future .
Vaccines are only effective if they are given, the data supporting their safety and effectiveness are abundant, and vaccines have eradicated several infectious diseases in parts of the world, saving countless lives.
However, public mistrust has grown due to misinformation and the anti-vaccine movement, threatening the maintenance of herd immunity and putting our most vulnerable populations at risk.
Declines in vaccination coverage can 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 rate of 56–75% in the United States may not be sufficient to achieve at least 80–90% coverage, the threshold considered necessary for herd immunity against SARS-CoV-2.
Although much of the burden of increasing vaccine coverage falls on governments and public health officials, the scientific community can also help by improving the efficacy and safety of mRNA vaccines.
Improving efficacy will reduce the acceptance needed for herd immunity, and improving safety will deter media coverage of adverse events, thereby reducing the fear of vaccination.
Decades of advances in mRNA design and nucleic acid delivery technologies, coupled with the discovery of neoantigen targets, have made mRNA vaccines an extraordinary tool in the fight against emerging and existing infectious diseases.
Two mRNA vaccines against SARS-CoV-2, developed at revolutionary speed and providing superior protection rates, are expected to end the COVID-19 pandemic.
Furthermore, these vaccines elevate LNP and RNA therapeutics from niche market products to preventive treatments successfully implemented in large populations.
The resulting extensive safety and efficacy data, as well as successful regulatory approvals. We can be optimistic that mRNA therapy will have the potential to change modern medicine’s approach to vaccination, cancer immunotherapy, and protein replacement therapy.
1. mRNA vaccines for infectious diseases: principles, delivery and clinical translation. Nat RevDrug Discov. 2021 Aug 25 : 1–22.
What are unresolved issues on mRNA vaccines?
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