mRNA vaccines are the best option for rapid response applications
Vaccinations is the most effective public interventions to save the lives of millions every year by controlling the spread of infectious diseases. Live attenuated and inactivated vaccines provide robust immunogenic response against polio, measles, mumps, rubella etc. But the vaccine development was still a hurdle against those pathogens which evade immune system viz. Hantavirus, Herpesvirus, HIV, SARS, MERS, Ebola and Zika virus.
There was a need for “On Demand” technology platform for rapid response applications.
Research work had been going on mRNA modalities for the last two decades. Technological advancements in molecular biology and chemistry have mostly contributed to the stability and delivery of mRNAs. These could attain a higher potency and safety in order to sustain a long -lasting response during clinical trials.
In the past few years, the mRNA vaccines are experiencing a burst in basic and clinical research. Majority of them are focused on cancer research/ applications and wide variety of infectious disease pathogens, including influenza virus, Ebola, Zika, Streptococcus spp. and T. gondii etc. Advancements in modulating the innate immune sensing mechanism not only aid in the active vaccination process, but also be used in passive immunization.
Recombinant monoclonal antibodies, passive therapeutics, are rapidly transforming the pharmaceutical markets and have become one of the most successful therapeutic classes in treating autoimmune disorders, various infections, osteoporosis, hypercholesterolemia and cancer. High-cost protein production pose the limitation to wide spread accessibility. Antibody gene transfer technology could potentially overcome these difficulties, as they administer nucleotide sequence to the patients enabling in-vivo production of precisely folded and modified protein therapeutics.
A crucial need for rapid response vaccines was prompted during 2013-2016 outbreaks of Ebola and Zika. mRNA vaccine platform attains all the relevant features to fulfil the demand which has provided the confirmation during COVID-19 pandemic.
The synthetic landscape of mRNA, has the capability to design and develop vaccines can be deployed for large scale production in a rapid response manner. These vaccines mimic the infection in situ by expressing antigen to induce both humoral and cytotoxic immune response. It’s special intrinsic adjuvant properties recognised by a key element, the pattern recognition receptors (PRRs).
mRNA a non-integrated platform without potential risks involved, has the capability to fill up the gaps of vaccine development in a rapid & scalable manner, including its economical manufacturing to get the higher yields, in vitro by transcriptional reactions.
It is based on the principle that genetic information of gene of interest encoded is translated by ribosomes to form required protein antigen to be used as vaccine in situ.
https://actascientific.com/ASMI/pdf/ASMI-04-0797.pdf DOI: 10.31080/ASMI.2021.04.0797
Translation dependent stability of mRNA is influenced by various coding sequences, which is a critical concern for vaccine stability. Codons modulate the protein expression, their kinetics and translational accuracy in protein folding including cryptic T-cell epitopes present in alternative reading frames. The advanced & optimized innate immune response is promoted substantially to increase the vaccine production in DCs, and to avoid adverse effects. DCs are targeted for transfection by mRNA, both in vivo and ex vivo. The ex vivo loading method is pursued in cancer treatment.
The nucleoside vaccine format induces strong CD8+T cell response with substantial presentation of MHC class-I molecules, along with generation of potent neutralizing antibodies.
Innate immune sensing mechanism is involved to produce the vaccine response to engage both the innate and adaptive arms of the immune system.
Self-adjuvating feature through sensing machinery is capable to induce a barrier against viral infections, through various receptors (RIG-I, MDA-5) help in the exogenous sensing process by activation of 1 IFN, which induces transcriptional and post transcriptional changes to augment the antiviral state.
Vaccine development, by conventional methods, is normally a longer and expensive process. Attrition is higher, it takes multiple candidates and many years to produce a licensed one, which follows a linear sequence of steps with multiple pauses for data analysis and manufacturing process checks. In opposite to the conventional vaccines, the COVID-19 mRNA vaccines are being prepared on the novel platforms to combat the disease.
COVID-19 pandemic is exploded in Dec 2019 in Wuhan, China and still going on. The death toll around the world is >3.5 million as of 1 June 2021. The pandemic has collapsed the healthcare system all over the world, shut down many businesses rendered many people jobless. Countries are still imposing new lockdown measures while facing the different phases/ waves of the pandemic.
The SARS CoV-2 genome was sequenced in January 2020. Pfizer & BioNTech and Moderna have successfully developed the mRNA vaccine candidates BNT162b2 and mRNA-1273 amid pandemic. The first clinical trial began in March 2020. The encoded antigen S-2P glycoprotein is encapsulated by LNPs, used in mRNA. The vaccine efficacy is achieved as 94-95%, which is 30% more than the set criteria limit. Pfizer & BioNTech is authorized for the first time by MHRA regulators (UK) to market their product for mass immunization. The interim guidance has been developed by WHO based on data emerged during clinical trials and the advice issued by the Strategic Advisory Group of Experts on immunization on January, 2021 for both the leading mRNA vaccine candidates.
The directions for the consideration of this new platform for widespread use are; cGMP manufacturing, regulatory guidance, safety aspects and vaccine efficacy.
The rapid development of COVID-19 mRNA vaccines are the emerging trends in the field of novel vaccines against the infectious diseases.
The current published data and development made on the COVID-19 vaccine has also provided the insights for commercialization of this novel technology in the field of cancer vaccines, universal flu vaccine, and other rapid response vaccines.
Ex vivo manipulations of the DCs could be a powerful tool to treat cancer in personalized medicines.
The viral replicons and their co-expression would provide a better understanding about the new generation vaccines. Emerging RNAi field provides siRNA imaging technology to work on their delivery by LNPs have shown that the complexed RNA enters the immune cells and help suppress the IFN response. This manipulates the RNA polymerase fidelity a completely new concept could be applied to the new generation RNA vaccines.
RNAs are versatile and being able to provide a wide range of opportunities for future improvements.
RNAs easily bypass the inherent potential safety limitations unlike live attenuated vaccines. This technology has the potential to enable new products because of its synthetic nature, cell free manufacturing approach.
The modern vaccine design is based on genetic engineering, immunology, structural biology, and system biology. The need of conventional vaccines seems unmet because in some chronic infections; the pathogen lapses the adaptive immune response or require active cellular immune response against the emerging diseases like Zika, Ebola, Nipah, and pandemic influenza. The unpredictable emerging and re-emerging outbreaks almost every year with high morbidity and exponential spread could create substantial social impacts. In those circumstances the vaccine ‘on- demand’ approach is highly desirable.
Understanding of the sequence events of antigen expression, innate and adaptive activation responses could further guide developing mRNA portfolios with efficient delivery systems. This will undertake different applications, such as delivery of vaccine antigen vs. therapeutic molecules (nano antibodies), prophylactic vs. personalized therapeutics, infectious disease vs. host disease etc.
mRNA will be continued as future prophylactic/ therapeutic for various ailments and disorders, with the emphasis on the delivery systems to increase the efficiency in targeting the infection.
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