Accelerate the development of covid-19 vaccine! Cooperation among pharmaceutical enterprises is crucial

In response to sars-cov-2, the long-term solution is to successfully develop a safe, effective and quality controlled vaccine, and actively prevent through large-scale vaccination to protect all countries from the harm of sars-cov-2The specific needs of different countries and regions in the world for vaccines, as well as the prevalence of covid-19, are characterized by wide geographical diversityTherefore, a variety of effective vaccine research and development paths are neededCollaboration between biotech companies and pharmaceutical companies is crucialIn order to effectively prevent sars-cov-2 infection, it depends on the complete research and development path of effective vaccine research and developmentTherefore, it requires the industry, government and academia to work together to complement each other's advantages and win-win cooperation< br / > speed up R & D: NIH launched the activ cooperation plan < br / > in April this year, at the critical moment of fighting against the covid-19 pandemic, the National Institutes of Health (NIH) announced that through the public-private partnership (PPP model), it has carried out extensive cooperation between multiple federal research institutions and 16 pharmaceutical companies, Coordinate and accelerate the development of covid-19 therapeutic drugs and vaccinesRecently, DrLawrence Corey, Professor of medicine and laboratory medicine, University of Washington, founder of clinical trial network of HIV vaccine, DrJohn Rmascola, director of National Institute of allergy and infectious diseases, DrAnthony Fauci, director of NIAID, DrFrancis SCollins, director of NIAID, A joint article was published in science magazine, detailing the activ program and the development progress of several candidate vaccines covered by the program< br / > this cooperation plan, called activ, will establish a cooperation framework that prioritizes vaccines and candidate drugs, simplify clinical trials, coordinate registration process, make overall planning, give full play to advantages and pool efforts through effective cooperation mechanism, so as to achieve the goal of rapid response to the covid-19 pandemic and potential future pandemicsActiv plans to generate basic safety and effectiveness data for several candidate vaccines in a synchronous and parallel way, accelerate the development of multiple vaccine platforms, and accelerate the goal of vaccine approval and distributionThe < br / > activ program sets up four fast track areas of concern, each of which will be led by a powerful working group of senior scientists representing the government, industry and academia For each fast track, there are specific detailed measures < br / > data source: reference [3], content team drawing of Wuxi apptec < br / > at present, we do not know the details of protective immune response against sars-cov-2 From the data of sars-cov-1 and recently sars-cov-2 patients, it is proved that patients will have relatively high immune response after infection, especially the antibody response to the spike protein that mediates the virus into cells However, in vivo data on the type or level of immunity required to prevent subsequent reinfection, as well as the potential duration of related protection, are still poorly understood In the animal model of sars-cov-1, the recombinant subunit protein, virus and nucleic acid vector vaccine were used for immunization, and the neutralizing antibody was passively transferred to the spike protein, which proved to have protective effect on experimental infection But protecting against infection, regulating viral replication, and changing the end point of disease progression are different These data make people optimistic that the high immunogenicity vaccine will produce the antibody response needed for protection with high quality and quantity However, no matter in animal challenge model or in human coronavirus disease, the role of T-cell immunity in prevention or improvement of early infection is still unknown These factors are the reason why we can't only focus on one vaccine in vaccine development < br / > it is the most important goal to ensure the high safety of vaccine for any kind of vaccine used for extensive vaccination Theoretically, if the defective vaccine is inoculated, there may be a risk of aggravating the infection of sars-cov-2 It has been reported that felines are infected with coronavirus, and this phenomenon has also been observed in some animal models challenged by sars-cov-1 vaccine These preclinical data show that the aggravation of vaccine related respiratory syndrome is due to the combination of poorly protected antibodies (producing immune complex deposition) and Th2 helper cell biased immune responses It is necessary to further explore the potential mechanism of vaccine induced immune enhancement and the methods to minimize this risk Therefore, it is very important to construct the correct antigen which can trigger the functional and effective antibody This is an important lesson learned from the accident of vaccine induced lower respiratory diseases in infants vaccinated with formalin inactivated respiratory syncytial virus (RSV) vaccine in the late 1960s At present, animal models of sars-cov-2 infection are being developed It is expected that these animal models can better understand the protection related immune response < br / > clinical and immune endpoints < br / > how to define the primary endpoint of covid-19 vaccine efficacy also needs to be discussed The two most frequently mentioned cases include: (1) prevention of infection defined by seroconversion, and (2) prevention of diseases with clinical symptoms, especially improvement of disease severity, including the frequency of diseases requiring high-intensity medical care; and the reduction of the number of inpatients according to strict evaluation results This requires a careful assessment of the impact of vaccination on the severity of the covid-19 disease in various epidemiological and medical settings in young and older populations, as well as in ethnic minorities with inadequate health care services All these problems need to be evaluated under these initial effectiveness test conditions Reaching these end points may also be related to the reduction of transmission rate on a group basis < br / > it is estimated that asymptomatic infection accounts for 20% to 40% of the total cases of covid-19 Therefore, the main end point related to disease reduction requires more registrants to participate in clinical trials Initial efficacy trials may require a large number of initial registrations, along with ongoing monitoring of serological and clinical endpoints Due to the lack of accurate understanding of the incidence rate, a complex challenge is a major challenge for clinical trials in the end point of serology A key requirement of this multi trial strategy is to establish an independent laboratory with similar or identical validation of serological tests, so as to establish a coordination bridge between multiple vaccine products and multiple vaccine efficacy tests These laboratories should be required to be used in all clinical trials, or to share key specimens from trials The parameters that distinguish the immune response caused by vaccination from that caused by infection are being studied in depth At present, it is urgent to develop experiments to solve this problem < br / > vaccine effectiveness tests need to be comprehensively evaluated from the perspective of benefits and risks The possibility of re exposure of sars-cov-2 is much higher than that of sars-cov-1, which disappeared from community communication Therefore, the potential enhancement of re exposure needs to be evaluated in the long term This requirement does not conflict with approval based on the above endpoints; however, the initial vaccine cohort should be tracked for a longer period of time Because of the decline of immunity in the population infected with coronavirus, it is necessary to further explore the persistence of clinical and serological endpoints Coronavirus has a single strand RNA genome with a relatively high mutation rate Although there are some genetic drift in the development and evolution of sars-cov-2 epidemic, up to now, no significant mutation of spike protein has been observed, especially in the areas where antibody neutralization is very important This situation makes the industry cautious and optimistic about the vaccine currently designed, which is likely to effectively fight against the epidemic virus strains in the next 6-12 months < br / > data source: reference [2], organization participating in the activ plan (data source: reference [3], organization participating in the activ plan) < br / > it is suggested that a controlled human challenge test can be carried out, with a few volunteers vaccinated and then challenged with sars-cov-2 Such experiments, if designed to define potential immune related substances or to screen out less effective vaccine methods, may have practical value However, in terms of pathophysiology and safety, this method is flawed Although the risk of serious disease or death in young healthy individuals with covid-19 is quite low, it is not zero; so far, there is no proven treatment that can save volunteers with related complications According to the design, sars-cov-2 challenge virus strain will cause mild illness in most volunteers, so it may not be able to repeat the pulmonary pathophysiological symptoms observed in some patients In addition, some of the efficacy in young healthy adults could not predict similar efficacy in older people with major covid-19 disease-related cofactors, nor could it prove to reduce the transmission to major susceptible people Whether such experiments are worth continuing or have a beneficial impact on vaccine development schedules requires careful evaluation by an independent team of ethicists, clinical trial experts and vaccine development experts < br / > vaccine platform < br / > it is encouraging that a number of vaccine development work has progressed rapidly, and several major vaccine platforms are advancing to clinical evaluation These include traditional recombinant proteins, replication and non replication viral vectors, as well as nucleic acid DNA and mRNA methods Each of these vaccine platforms has its own advantages and limitations The important characteristics of these vaccine platforms include production speed and flexibility, safety and reactivity, humoral and cellular immunogenicity characteristics, immune sustainability, production scale and cost, vaccine stability and cold chain requirements There is no single vaccine or vaccine platform that can meet global needs alone, so a multi pronged strategic approach is essential < br / > several companies are developing nucleic acid based vaccines, including Moderna, bintech / Pfizer, curavac (mRNA based) and inovio (DNA based) DNA vaccine and mRNA vaccine can be generated rapidly according to the virus sequence, so the progress is faster At present, the best immunogenicity of DNA requires electroporation or syringe delivery device, so that DNA can enter cells MRNA vaccine uses lipid nanoparticles to protect and deliver mRNA, which can be used as adjuvant of immunogen effectively However, it is necessary to solve the problem of scalability and temperature stability of these lipid nanoparticles Although the early clinical experience of nucleic acid vaccine is very rich, no vaccine has been widely used Therefore, although there is no lack of optimistic hope on the way forward, there are still some uncertainties It is necessary to evaluate the immunogenicity and safety of these products as soon as possible, and solve the problems faced by the lack of business experience < br / > the vaccines that Sanofi and Novavax are developing use the traditional recombinant protein technology to express spike protein For this kind of vaccines, although it takes longer to establish the cell line for production than the nucleic acid vaccine, the protein and protein particle vaccines, including hepatitis B, human pasteurevirus, varicella zoster and influenza vaccines, have been approved, At the same time, we have solid business experience Protein vaccine needs an effective adjuvant, which is essential to induce Th1 immune response; however, the availability of some adjuvants may be limited < br / > viral vector vaccine packs the concerned viral gene code into one of several well characterized vectors, including adenovirus (AD) and vesicular stomatitis virus (VSV) Recently, it has been proved that replication defective adenovirus 26 (Rad26) can be effectively prevented