A peer-reviewed paper published in The New England Journal of Medicine provides data from the much-anticipated COVE study, which evaluated mRNA-1273, a vaccine candidate against COVID-19 manufactured by Moderna, Inc. Results from the primary analysis of the study, which will continue for two years, provide evidence that the vaccine can prevent symptomatic infection.
Among the more than 30,000 participants randomized to receive the vaccine or a placebo, 11 of those in the vaccine group developed symptomatic COVID-19 compared to 185 participants who received the placebo, demonstrating 94.1 percent efficacy in preventing symptomatic COVID-19.
Brigham and Women’s Hospital served as a site for the trial as part of the COVID-19 Prevention Network (CoVPN), funded by the National Institutes of Health. In addition, Lindsey Baden, MD, an infectious diseases specialist at the Brigham and an expert in vaccine development for viral diseases, served as co-principal investigator for the study and lead author of the paper.
“Our work continues. Over the next months, we’ll have increasing amounts of data to better define how this vaccine works, but the results so far show a 94.1 percent efficacy. These numbers are compelling,” said Baden.
“And, importantly, the data suggest protection from severe illness, indicating that the vaccine could have an impact on preventing hospitalizations and deaths, at least in the first several months post-vaccination.”
The study enrolled 30,420 adult participants at 99 U.S. sites, including over 600 participants enrolled at the Brigham. Eligible participants were 18 years old or older with no known history of SARS-CoV-2 infection, and whose locations or circumstances put them at appreciable risk of SARS-CoV-2 infection and/or high risk of severe COVID-19.
The race and ethnicity proportions of the trial were generally representative of U.S. demographics (79 percent white; 10 percent Black or African American; 20 percent Hispanic or Latino participants).
Participants received their first injection between July 27 and Oct. 23, 2020, followed by a second injection 28 days later. Each injection, given intramuscularly, had a volume of 0.5 mL, containing 100 μg of mRNA-1273 or saline placebo.
In the placebo group, 185 participants developed symptomatic COVID-19 illness; in the vaccine group, 11 participants did. In secondary analyses, the vaccine’s efficacy was similar across groups of key interest, including those who already had antibodies against SARS-CoV-2 at the time of enrollment (indicating previous infection with COVID-19) and among those who were 65 years of age or older. Thirty participants had severe COVID-19 – all in the placebo group.
Starting from randomization, cases of COVID-19 and severe COVID-19 were continuously monitored throughout the trial by the Data Safety Monitoring Board, empaneled by the NIAID. Participants were closely monitored for adverse events in the weeks following their injection. Investigators have collected and will continue to collect data on any serious adverse events or adverse events that require medical attention through two years post-injection.
Overall, reactions to the vaccine were mild—about half of recipients experienced fatigue, muscle aches, joint pain and headaches, more so after the second dose.
In most cases, these effects started about 15 hours after the vaccine and resolved after two days without sequelae. A similar number of adverse events were reported in the placebo and vaccine groups.
“While these results are encouraging, they are limited by the short duration of follow-up so far. Longer term data from the ongoing study may allow us to more carefully evaluate the vaccine’s efficacy among different groups, determine the impact on asymptomatic infection, understand when immunity wanes, and determine whether vaccines affect infectiousness,” said Baden.
“But we shouldn’t lose sight of the progress that we have made, which shows what is possible when we come together to tackle an immensely challenging problem.”
The mRNA vaccine is the delivery of mRNA to cells that express the protein that produces it, thereby expanding the immunity of the organism . It does not require any nuclear localization signal, transcription, and integration into the genome is not possible, which avoids any possible therapeutic mutations [289, 290].
There are two main types of mRNA vaccines available, those that are self-amplifying and those that are non-replicating mRNA . Self-amplifying mRNA vaccines are usually based on the genome of the genus alphavirus, where the gene encoding the RNA replication mechanism is intact and the structural protein-coding gene of the protovirus is replaced with mRNA encoding the antigenic protein [292, 293].
Non-replicating mRNA vaccines are in vitro transcribed sections of complete mRNA encoding antigenic proteins, including 5′ and 3′ untranslated regions, and poly(A) tail to stabilize the mRNA and promote transcription [294, 295]. The mRNA vaccine is synthesized by in vitro transcription techniques using plasmid DNA or other DNA fragments containing the open reading frame of the target protein as a template .
Since mRNAs contain cap structures at the 5′ end and Poly(A) at the 3′ end, the addition of these components is generally required after in vitro transcription of the synthesized mRNA. There are also many current studies on the synthesis of mRNA vaccines in vitro by chemical modification. And for mRNA vaccine delivery, it can be done by electroporation, liposome nanoparticle delivery system, polymer delivery system [297,298,299,300].
For example, Nucleoside-modified mRNA greatly improves mRNA stability and can regulate the half-life of mRNA drugs in vivo; liposomal nanoparticles can envelope mRNA, further improving stability and also efficiently complete intracellular delivery of mRNA [296, 301].
The first candidate COVID-19 vaccine was mRNA-1273 developed by Moderna. After Chinese scholars shared the gene sequence of the SARS-CoV-2 on January 11, 2020, NIH and Moderna began development of the mRNA-1273 vaccine with funding from The Coalition for Epidemic Preparedness Innovations (CEPI).
On February 7, production of the first clinical batch of the vaccine was completed, and on March 4, a Phase I clinical trial was approved by the FDA. This experiment provided important data on the safety and immunogenicity of mRNA-1273 by recruiting 45 healthy adult volunteers aged 18 to 55 years.
The clinical phase I trial conducted by Moderna had three dose groups, 25μg, 100μg, 250μg, and expanded the six groups in the older and the elder. On May 7, the FDA approved the study for a Phase II clinical trial. A third phase of the study is planned for early summer.
The platform used for this vaccine is mRNA. In past studies, the safety of Phase I clinical trial species of five other respiratory viruses (two pandemic influenza viruses, RSV, hMPV, and PIV3) has been proved [302, 303]. mRNA is an information molecule, and Moderna used the sequence of the virus to design messenger RNA vaccines, rather than studying the virus itself.
mRNA platforms have significant advantages in terms of speed and efficiency. mRNA can span basic science, manufacturing, and clinical development. After verifying the safety and efficacy of mRNA-1273, it will be put into mass production.
On May 18, data from the Phase I clinical trial published on Moderna’s webpage showed that, after two doses, all participants in the 25 μg and 100 μg dose cohorts evaluated to date had seroconversion rates that met or exceeded the levels of conjugated antibodies in their recovery serum.
In the 25 μg and 100 μg dose cohorts, mRNA-1273 elicited neutralizing antibody titers in all eight initial participants, meeting or exceeding the neutralizing antibody titers typically seen in recovery serum. mRNA-1273 was overall safe and well tolerated. The only grade 3 adverse event that occurred in the 25 μg and 100 μg dose cohorts was a grade 3 erythema around the injection site in a participant in the 100 μg dose group.
By far, the most notable adverse events occurred at the 250 μg dose level, with three participants experiencing grade 3 systemic symptoms only after the second dose. All adverse events are transient and can resolve themselves. No grade 4 adverse events or serious adverse events are reported .
DNA vaccines are delivered into the body and are taken up by surrounding tissue cells (e.g., myocytes), antigen-presenting cells (APCs) or other inflammatory cells . Plasmid DNA molecules ingested by tissue cells such as myocytes are then transcribed into mRNA in the nucleus, which is then moved into the cytoplasm for translation into antigenic protein molecules .
The antigenic protein molecules released by the cells into the tissue interstitium are captured by APCs and processed into antigen-peptide delivery to T cells, initiating an immune response . APCs from peripheral lymphatic organs also directly uptake nucleic acid vaccines, express antigens and deliver them to T cells, triggering an immune response.
Dendritic cells are the most important antigen-delivering cells in nucleic acid immunity, while B cells are not involved in the antigen-delivering process . After triggering an immune response, the cytotoxic T-cell (CTL) response recognizes and kills myocytes expressing exogenous antigens, causing myocytes to lyse and release intracellular antigens, which APC obtains directly from the injection site to initiate the subsequent immune response.
The combination of several pathways allows the DNA vaccine to stimulate T lymphocytes via the histocompatibility complexes MHC I and MHC II, and to activate B lymphocytes. Tissue cells such as myocytes may act as storage plasmids and regular release during the immune process [25, 309].
Inovio had developed a Phase 2 vaccine for Middle Eastern respiratory syndrome-related coronavirus, has designed INO-4800 using the DNA medicines platform. INO-4800 matches the DNA sequence of the virus precisely. On April 20th, Clinical Phase I trial has been approved by the FDA.
DNA medicine consists of optimized DNA plasmids or recombined by computer sequencing techniques and designed to produce specific immune responses in the human body. Inovio’s DNA drugs use Inovio’s patented handheld smart device, CELLECTRA®, to deliver optimized plasmids directly into cells by intramuscular or intradermal injections.
CELLECTRA uses a short electrical pulse to reversibly opens small pores in the cell to allow plasmids to enter by using a short electrical pulse to reversibly. Once in the cell, the plasmids begin to replicate, thus reinforcing natural response mechanisms.
The use of CELLECTRA device makes sure that the DNA drug enters cells directly, where it can immediately initiate an immune response. Inovio’s DNA drugs do not interfere with or alter a person’s DNA in any way.
The advantages of Inovio’s DNA drug platform are fast development and production of DNA drugs, good product stability, no refrigeration for storage and transport, strong immune response, safety and tolerability.
The main mechanism of recombinant COVID-19 vaccines (adenovirus vectors) is the use of genetic engineering techniques to introduce and express genes encoding pathogenic protective antigens into adenovirus vaccines . The first step is to select the highly characteristic protein structures on the surface of the pathogenic virus, that is, these protein structures stimulate the immune system to produce antibodies.
For coronaviruses, the protrusion on the surface of the viral shell (S protein) is a target protein. Next, find the gene that encodes the S protein [311, 312]. For DNA viruses, the corresponding DNA fragment can be found directly; for RNA viruses, the corresponding RNA has to be found and translated into DNA fragments [313, 314].
What’ more, the encoded genes are fused into the DNA of the adenovirus and allowed to enter the human cell via the adenovirus as a vector. Finally, these coding genes synthesize some of the characteristic proteins of the pathogenic virus in the body, which induces strong humoral and cellular immunity and induces the body to produce specific antibodies, which are people’s immunity against the pathogenic virus .
Ad5-nCoV, a recombinant vaccine (adenovirus vector type 5) studied by the Beijing Institute of Biotechnology and three other Chinese research institutions with support from CanSino Biologics Inc. . A clinical phase I trial (NCT04313127) has already started on March 15, 2020, which is a single-center, open-label, dose-escalating, phase I clinical trial in a healthy population aged 18 to 60 years to assess the safety, adverse effects and immunogenicity of a novel recombinant coronavirus vaccine.
One hundred eight volunteers were assigned to three groups and received either an intramuscular injection of the experimental vaccine in the deltoid muscle or a placebo. The experimental group was divided into high school and low three dose groups, and the estimated completion time of this clinical trial is December 2020.
The study conducted by Wei Chen et al. was published in The Lancet on May 22nd, and the safety, tolerability and immunogenicity of Ad5-nCoV were reported . The main findings so far show that Ad5-nCoV is safe, well-tolerated in humans, and able to cause the immune response of immune system to COVID-19.
Further trials will be required to assess whether the vaccine is effective in preventing neo-coronavirus infection. In the article, it was reported that within 7 days of Ad5-nCoV vaccination, 30 people in the low-dose group (83%), 30 people in the medium-dose group, 30 People (83%) and 27 people (75%) in the high dose group experienced at least one adverse effect.
These adverse reactions included more than half (54%, 58/108) of the vaccines experiencing mild pain at the injection site. Fever (46%, 50/108), fatigue (44%, 47/108), headache (39%, 42/108) and muscle pain (17%, 18/108). The results showed that each dose of vaccine was well tolerated and no serious adverse reactions were reported within 28 days after inoculation. Most adverse events were mild or moderate.
Reports of immunogenicity of Ad5-nCoV showed that within 14 days of vaccination, a certain level of immune response was triggered and antibodies were produced in the vaccines. The specific ratios were 16/36, 44%, in the low-dose group; 18/36, 50%, in the medium-dose group; 22/36, 61%, in the high-dose group.
Antibodies were produced at detectable levels in some subjects; the vaccine also triggered T-cell response. Twenty-eight days after vaccination, T-cell responses, or detectable levels of neutralizing antibodies, were present in the majority of vaccines. The specific ratios were: 28/36, 78% in the low-dose group, 33/36, 92% in the medium-dose group, 36/36, 100% in the high-dose group.
The researchers also found that if pre-existing immunity to adenovirus Ad5 existed in the subjects, the vaccine could be Weakening, such as reduced peak levels of immune responses and shortened persistence of immune responses.
Only 108 volunteers were involved in this study, and the short duration of the trial, as well as the lack of randomized controls, made it difficult to detect Adverse events, or the discovery of limitations in the protective power of vaccines. A phase II, randomized, double-blind, controlled clinical trial involving 500 volunteers is currently underway in Wuhan to see if the results of this phase I clinical trial can be replicated and if adverse events occur within 6 months of vaccination. What’ more, the population who are 60 years of age was also involved as subjects, for the first time.
ChAdOx1 nCoV-19, developed at the University of Oxford, consists of a non-replicating adenovirus vector and the S protein gene sequence of SARS-CoV-2 and is in Phase I/II clinical trials (NCT04324606). Adenovirus does not replicate in the host, making it relatively safe in children and individuals with underlying diseases.
In addition, based on the carrier of adenovirus has extensive organization orientation, including respiratory and gastrointestinal epithelium, both express the ACE of SARS-CoV-2 main parts of the receptor. Should always consider the carrier gene, however, rather than the possibility of genetically modified dominant immunogenicity .
According to the current results of animal experiments on ChAdOx1 nCoV-19 in rhesus monkeys, ChAdOx1 nCoV-19 vaccine does not prevent macaque monkeys from contracting the virus, nor does it prevent animals from spreading the infection to other animals. In this study, six rhesus macaques were vaccinated with the ChAdOx1 nCoV-19 vaccine, and after 28 days were exposed to the SARS-CoV-2 virus.
The researchers also compared them to three unvaccinated monkeys. As determined by the recovery of viral genomic RNA in nasal secretions, the researchers determined that all six macaques that were vaccinated with the vaccine were infected with the COVID-19. Compared with unvaccinated animals, the amount of viral RNA detected from this site in vaccinated rhesus monkeys had no difference.
COVID-19 synthetic Minigene vaccine
DC and CTL cells play a key role in viral clearance during the immune process, so it is important to induce vaccines that produce strong, long-lasting, cross-T cell responses [319,320,321,322]. This minigene can express a segment of amino acid residue peptide through viral infection or the synthesis of a minigene. Infected cells can sensitize immune cells and stimulate T-cell activity [323, 324].
Based on a detailed analysis of the viral genome and the finding for latent immunogenic targets, a synthetic mini-protein based on the conserved structural domains of viral structural proteins and multiprotein proteases was synthesized by the Shenzhen Geno-Immune Medical Institute. COVID-19 infection is mediated by binding of the spike protein to the ACE2 receptor and viral replication depends on the molecular mechanism of all these viral proteins.
This experiment intends to use the efficient lentiviral vector system (NHP/TYF) to develop and test a novel COVID-19 mini-genome based on a variety of viral genes, express viral proteins and immunoregulatory genes, modify DCs, and activate T cells . In this study (NCT04276896), the safety and efficacy of the LV vaccine (LV- SMENP) will be investigated.
reference link : https://link.springer.com/article/10.1186/s43556-020-00017-w
More information: Lindsey R. Baden et al, Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine, New England Journal of Medicine (2020). DOI: 10.1056/NEJMoa2035389