Abstract
The SARS-CoV-2 global pandemic has seen rapid spread, disease morbidities and death associated with substantive social, economic and societal impacts. Treatments rely on re-purposed antivirals and immune modulatory agents focusing on attenuating the acute respiratory distress syndrome. No curative therapies exist. Vaccines remain the best hope for disease control and the principal global effort to end the pandemic. Herein, we summarize those developments with a focus on the role played by nanocarrier delivery.
Original language | English (US) |
---|---|
Pages (from-to) | 215-239 |
Number of pages | 25 |
Journal | Advanced Drug Delivery Reviews |
Volume | 171 |
DOIs | |
State | Published - Apr 2021 |
Keywords
- COVID-19 vaccine
- Nanovaccine
- SARS-CoV-2
- mRNA vaccine
ASJC Scopus subject areas
- Pharmaceutical Science
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Nanocarrier vaccines for SARS-CoV-2. / Machhi, Jatin; Shahjin, Farah; Das, Srijanee et al.
In: Advanced Drug Delivery Reviews, Vol. 171, 04.2021, p. 215-239.Research output: Contribution to journal › Review article › peer-review
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TY - JOUR
T1 - Nanocarrier vaccines for SARS-CoV-2
AU - Machhi, Jatin
AU - Shahjin, Farah
AU - Das, Srijanee
AU - Patel, Milankumar
AU - Abdelmoaty, Mai Mohamed
AU - Cohen, Jacob D.
AU - Singh, Preet Amol
AU - Baldi, Ashish
AU - Bajwa, Neha
AU - Kumar, Raj
AU - Vora, Lalit K.
AU - Patel, Tapan A.
AU - Oleynikov, Maxim D.
AU - Soni, Dhruvkumar
AU - Yeapuri, Pravin
AU - Mukadam, Insiya
AU - Chakraborty, Rajashree
AU - Saksena, Caroline G.
AU - Herskovitz, Jonathan
AU - Hasan, Mahmudul
AU - Oupicky, David
AU - Das, Suvarthi
AU - Donnelly, Ryan F.
AU - Hettie, Kenneth S.
AU - Chang, Linda
AU - Gendelman, Howard E.
AU - Kevadiya, Bhavesh D.
N1 - Funding Information: Mainly two types of mRNA constructs have been evaluated: self-amplifying mRNA and non-replicating mRNA [ 286 ]. Both types of mRNAs are synthetically produced, encoding target antigens' 5′ and 3′ untranslated region, cap structure, and open-reading frame, through the use of a cell-free enzymatic transcription reaction. Self-amplifying mRNA vaccines possess genetically-engineered replication machinery that is obtained from the positive-stranded mRNA viruses [ 286 ]. Delivery of the intact mRNA vaccine from the injection site to the target cell cytosol for the initiation of protein translation is as important as manufacturing of the mRNA construct. mRNA is labile and prone to degradation primarily from nuclease activity within the cells; hence, efficient protection of the mRNA is critical during administration [ 285 ]. Lipid nanoparticles could serve as safe and compatible intracellular delivery platform for the development of successful mRNA vaccine. Lipid nanoparticles offer (i) sustained mRNA confirmation (iii) protection of mRNA cargos against nuclease degradation and; (ii) efficient cellular uptake for targeted mRNA delivery [ 17 , 276 ]. In the past, lipid nanocarrier system has delivered RNA for the therapeutic applications. In 2018, the first lipid nanoparticle formulated siRNA product Onpattro® was approved by the US FDA for the treatment of polyneuropathy caused by hereditary transthyretin-mediated amyloidosis, which established the standard for the clinical safety of lipid nanoparticle-based siRNA formulations [ 287 ]. Lipid nanoparticles are generally composed of ionizable lipids, cholesterol, PEGylated lipids, and phospholipids to deliver an mRNA construct. The ionizable cationic lipids create a lipid bilayer shell that allow mRNA encapsulation within an aqueous core for endosomal escape [ 288 ]. New-generation cationic lipids and lipoids are developed that maintain neutral or mild cationic charge at physiological pH to reduce nonspecific lipid-protein interactions [ 289 ]. Cholesterol provides stability to the lipid bilayer membrane and facilitates cellular transfection. PEGylated lipids serve to sterically stabilize the nanoparticles and reduce nonspecific protein bindings. Decoration of the outer surface with targerting moieties and encapsulation of multiple antigens for tailor-made immunization are additional advantages with lipid nanoparticles [ 290 ]. Several companies have used nanovaccine technology for the development of SARS-CoV-2 vaccines. Moderna, an mRNA-based biotechnology company, initiated the first mRNA nanovaccine using their patented nanovaccine technology (WO2017070626 and WO2018115527). Moderna first developed an mRNA vaccines that encodes the MERS-CoV antigens: (i) S or its fragment (S1); (ii) E, (iii) membrane (M); or (iii) nucleocapsid (N) protein. These vaccines are effective in inducing antigen-specific immune responses. Moderna encapsulated the mRNA mixture into the cationic lipid nanoparticles and intradermally injected the vaccine into mice, which lead to the encoding MERS-CoV S proteins' translation in vivo for the subsequent induction of humoral immune responses. The MERS-CoV mRNA nanovaccine encoding the full-length S protein reduced more than 90% of the viral load in the lungs and induced a significant amount of neutralizing antibody against MERS-CoV in the New Zealand white rabbits [ 291 ]. Research on MERS-CoV vaccines led to funding from CEPI (Coalition for Epidemic Preparedness Innovations) to manufacture an mRNA nanovaccine against SARS-CoV-2 (mRNA-1273). This led to the first mRNA nanovaccine to enter clinical trial ( NCT04283461 ) for SARS-CoV-2. In mRNA-1273 vaccine, two proline amino acids were substituted at 986 and 987 positions in the S2 cleavage site to maintain stability of the prefused S mRNA [ 291 ]. The findings from the Moderna SARS-CoV-2 vaccine trial raised optimism. In the preliminary Phase 1 clinical trial, Moderna investigated a dose-escalation study of mRNA-1273 in 45 healthy adults (18 to 55 years of age), who were vaccinated at two time points, 28 days apart, with three different doses (25 μg, 100 μg or 250 μg). Commensurately, antibody responses were highest with the higher dose after the first vaccination and titers were increased after the second vaccination. Serum-neutralizing activity was detected using pseudotyped lentivirus reporter single-round-of-infection neutralization assay (PsVNA) and live wild-type SARS-CoV-2 plaque-reduction neutralization testing (PRNT) assay. No participant had measurable neutralizing antibody responses before vaccination however all participants showed higher antibody responses after second vaccination in both PsVNA and PRNT assays. mRNA-1273 stimulated Th1-biased CD4 T cell responses in all participants. From the lower dose groups (50 μg and 100 μg), all the participants showed mild or moderate side effects. However, one or more adverse events were reported in few participants from the 250 μg dose group. Similar adverse events were presented in clinical trials with high dose of avian influenza mRNA vaccine (influenza A/H10N8 and influenza A/H7N9) manufactured by Moderna's lipid nanoparticle technology [ 292 ]. The Phase 1 clinical trial was expanded to included 40 older adults of 56 to 70 years or ≥ 71 years of age who received two doses of mRNA-1273 vaccine (50 μg and 100 μg). In this study, 100 μg dose induced higher antigen-binding and neutralizing antibodies in all the older participants while the associated side effects were mainly mild or moderate [ 293 ]. In Phase 2 clinical trial, Moderna is demonstrating safety and immunogenicity of mRNA-1273 in 600 healthy participants across all age groups (above 18 years) where participants will receive either 50 μg or 100 μg dose twice at 28 days interval with follow-up for 12 months after the second vaccination ( NCT04405076 ). Moderna has already initiated a Phase 3 clinical trial in collaboration with the National Institute of Allergy and Infectious Diseases (NIAID) in 30,000 young adult participants to test mRNA-1273 at 100 μg dosage. The primary endpoint of this study is prevention of symptomatic COVID-19 disease while the secondary endpoints include prevention of severe COVID-19 disease and infection by SARS-CoV-2 ( NCT04470427 ) [ 292 ]. On November 15, 2020, the interim results of mRNA-1273 Phase 3 clinical trial were released that comprised 95 cases of symptomatic COVID-19 where 90 cases belongs to the placebo group and 5 cases from the vaccinated group. The vaccine was found safe and well-tolerated and showed 94.5% efficacy in studied candidates with statistical significance [ 294 ]. Based upon the promising interim results of Phase 3 trial, Moderna received the US FDA EUA of mRNA-1273 for COVID-19 treatment [ 295 ]. Funding Information: We thank Doug Meigs, University of Nebraska Medical Center, for critical review of the manuscript. This work was supported by the National Institutes of Health R01 MH121402-01A1 ; R01 MH121402P01 ; R01 AG043540 , R01 AG043530 , P01 DA028555 , P30 MH062261 , R01 MH115860 , R01 NS034249 , R01 NS036126 , the Carol Swartz Emerging Neuroscience Fund and the Margaret R. Larson Professorship . Publisher Copyright: © 2021
PY - 2021/4
Y1 - 2021/4
N2 - The SARS-CoV-2 global pandemic has seen rapid spread, disease morbidities and death associated with substantive social, economic and societal impacts. Treatments rely on re-purposed antivirals and immune modulatory agents focusing on attenuating the acute respiratory distress syndrome. No curative therapies exist. Vaccines remain the best hope for disease control and the principal global effort to end the pandemic. Herein, we summarize those developments with a focus on the role played by nanocarrier delivery.
AB - The SARS-CoV-2 global pandemic has seen rapid spread, disease morbidities and death associated with substantive social, economic and societal impacts. Treatments rely on re-purposed antivirals and immune modulatory agents focusing on attenuating the acute respiratory distress syndrome. No curative therapies exist. Vaccines remain the best hope for disease control and the principal global effort to end the pandemic. Herein, we summarize those developments with a focus on the role played by nanocarrier delivery.
KW - COVID-19 vaccine
KW - Nanovaccine
KW - SARS-CoV-2
KW - mRNA vaccine
UR - http://www.scopus.com/inward/record.url?scp=85102116534&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85102116534&partnerID=8YFLogxK
U2 - 10.1016/j.addr.2021.01.002
DO - 10.1016/j.addr.2021.01.002
M3 - Review article
C2 - 33428995
AN - SCOPUS:85102116534
VL - 171
SP - 215
EP - 239
JO - Advanced Drug Delivery Reviews
JF - Advanced Drug Delivery Reviews
SN - 0169-409X
ER -