At the current stage of coVID-19 vaccine development worldwide, there are five technical routes: inactivated vaccine, adenovirus vector vaccine, recombinant protein vaccine, nucleic acid vaccine (including mRNA and DNA vaccine) and attenuated vaccine.
By Gao Yushan. Photo by “Unsplash”
On August 8, Hillhouse HCare Global Health Industry Summit, Hillhouse Capital partner Elnuocin Shared the latest development of global COVID-19 vaccine at the main forum.
The current technical routes of coVID-19 vaccine development worldwide are divided into five categories: inactivated vaccine, adenovirus vector vaccine, recombinant protein vaccine, nucleic acid vaccine (including mRNA and DNA vaccine) and attenuated vaccine.
Among them, the most prominent advantages of inactivated vaccine are good safety, low cost and rapid clinical progress.
Adenovirus vector vaccine has better safety, lower cost and faster progress, but its effectiveness needs to be verified by phase III clinical results.
The recombinant protein vaccine is superior in safety, efficacy and cost.
At present, mRNA vaccine has seen preliminary efficacy, safety needs to be further tracked, and production cost is relatively high. However, novel Coronavirus mutation has a strong ability to deal with it, because it is a good adjuvant in itself, so other adjuvants are not needed.
Key indicators used to compare coVID-19 vaccines include protection, duration of efficacy, and safety.
For the protection effect, the titer of neutralizing antibody is mainly concerned.
The duration of the effect depends mainly on whether the T-cell immunity is activated;
For safety, the main concern is fever.
Representative enterprises are China Biological group and Sinovac biological.
The titer level of neutralizing antibodies produced after use is around 100. It is uncertain whether inactivated vaccines with aluminum adjuvant can activate T-cell immunity, and the duration of protection is uncertain.
Data so far show that such vaccines are safe, and further data will be released at the end of August;
Sinovac is already in Brazil and Bangladesh;
Zhongsheng group (Wuhan Institute, Beijing Institute) has entered phase III clinical trials respectively in the United Arab Emirates and is expected to be approved by the end of 2020 if it goes well.
Adenovirus vector vaccine
Representative companies are Concino And Astrazeneca.
Mainly targeting full-length S protein, it can produce about 8 types of neutralizing antibodies. The phase II clinical data of Consino showed that adenovirus vector vaccine can stimulate T cell immunity, which is very prominent.
Astrazeneca’s adenovirus vector vaccine also has t-cell immunity, and it also has a relatively high antibody titer, around 200.
Astrazeneca’s adenovirus vector vaccine is the fastest in the world to enter phase III clinical trials, with some phase III data expected to be available for emergency use as soon as September.
Kang Xinuo biological vaccine could activate T cell immune adenovirus vector, the onion parody show a p value is 0.001, that is very significant, indicated that such vaccines if effective, protective effect may be relatively long duration, safety, high dose group in 8% level 3 (G3) fever (38.5 to 39.5 ℃), within the acceptable range.
The early neutralizing antibody titer of the patients recovered from Sinovac biological test was about 20-60. The neutralizing antibody titer of the mouse model was 1500, that of the rats was 2000, and that of the monkeys was 60.
In the monkey challenge experiment, the neutralizing antibody titer quickly climbed to 200-400.
Recombinant protein vaccine
On behalf of the enterprise clover, Intelligent flying biology, Novavax.
The Novavax vaccine has a neutralizing antibody titer of around 3000-4000, which is by far the highest neutralizing antibody titer in human clinical trials.
It is currently in phase II clinical practice and is expected to be approved in the first half of 2021.
Domestic recombinant protein vaccines adopt different antigen designs, and in general, the titer of medium and antibody is very high. Zhifeibio’s vaccine has entered the phase II clinical stage, while clover’s recombinant protein vaccine is in the phase I clinical stage, and is expected to be approved for large-scale use in 2021-2022.
Zhifei bio-recombinant protein vaccine in the monkey experiment, neutralizing antibodies can reach 2000.
Using the patented technology platform of “protein trimerization”, Clover successfully developed the “S protein trimerization” vaccine to keep the result and antigenicity of the novel coronavirusS protein natural trimerization, and is carrying out phase I clinical trial in Australia.
Currently, the DNA vaccine developed by Inovio, a UN company, has entered phase I clinical trials, and the neutralizing antibody titer is 100 in a preclinical mouse model.
The Novavax recombinant protein vaccine achieved 10, 000 antibody titers in a mouse model, 10, 000 antibody titers in a baboon model on day 35, and 10, 000 antibody titers in a cynomolgus monkey.
This week reported Novavax recombinant protein vaccine clinical stage I data, 5 micrograms of dose, neutralizing antibodies of 3906 (4.0 times been patient neutralizing antibody), 25 micrograms dose neutralizing antibodies can reach 3305 (3.4 times been patient neutralizing antibody), although due to the difference of test method used Novavax/Baylor measured rehabilitation of the patients of neutralizing antibody degrees 6-10 times the Moderna and BioNtech reported the rehabilitation of the patients of neutralizing antibody drop degree;
However, compared with other vaccines, the titer of neutralizing antibody of recombinant protein vaccine is still recognized to be the highest.
In addition to high antibody titer, NovavaxI clinical data also confirmed that the adjuvant containing saponins significantly activated Th1 cell immunity, indicating a longer duration of vaccine protection.
It also avoids the activation of Th2 cell immunity, and according to the company’s hypothesis, the expected ADE risk is relatively small.
Inovio USES a full-length S-protein DNA vaccine. Nine T-cell epitopes were identified by Inovio, of which only six were in the RBD region and three were absent, theoretically indicating that The T-cell immunity activated by S-protein antigen might be more comprehensive.
The current Inovio/ Ethicin DNA vaccine has a neutralizing antibody titer of 100 in mice.
Many enterprises at home and abroad are developing the novel coronavirusS protein or RBD protein. In a word, the technical route is as follows: the mRNA sequence expressing the novel coronavirusS protein or RBD protein will be wrapped by liposome nanoparticles, then delivered to the cell, and the novel Coronaviruse-related protein will be expressed in the body to play the role of preventive vaccine.
The most advanced in the world is Moderna, which will enter phase II clinical trials at the end of May, 2020, and then phase III clinical trials at the end of July, making it the world’s first PHASE III clinical NCOVID-19 vaccine, which is expected to be approved for market at the end of this year.
The rapid follow-up includes BioNTech, currently in phase II clinical;
CureVac is currently in phase I;
TranslateBio/Sanofi in the preclinical phase.
The fastest progress in China is that of Suzhou Abogen, which will enter phase I clinical practice at the end of June 2020. The partners are Chinese Academy of Military Sciences and Watson Biology.
At present, other domestic enterprises including Zhuhai Lifanda, Shanghai Siwei and Hangzhou Xihai are still in the pre-clinical stage.
Moderna and BioNTech mRNA new crown vaccines are revealed relatively complete phase I clinical data, Moderna by protein S length, varieties of candidate phase I clinical data show the excellent neutralizing antibody induction ability, high dose group of 43 days after immunization, the neutralizing antibody degrees respectively so as to recover the patient’s serum neutralization antibody of 2.2 times and 4.1 times.
BioNTech also showed the ability of neutralizing antibody induction in phase I clinical data. The titer of neutralizing antibody in the medium and high dose groups was 1.8 and 2.8 times of that in the serum of recovered patients after immunization, respectively.