China has developed the world's first COVID-19 mucosal vaccine, can it prevent "breakthrough infections"?

Mucosal immunity is the biggest advantage of inhaled vaccines, but the relevant data have not yet been published | Ling Jun source | "Medical Community" public account

In the past week, two indigenous COVID-19 vaccines have recently been approved by the State Food and Drug Administration for "emergency use", including the world's first inhaled COVID-19 vaccine , inhaled Ad5-nCoV

For the upcoming autumn and winter high incidence of respiratory infectious diseases, as early as the beginning of this year, health departments in Europe and the United States began to discuss the immunization strategy for the second half of the year, and finally two bivalent (Omikron/original strain) mRNA vaccines were recently approved, which is the only bivalent COVID-19 vaccine

Back in China, sequential vaccination may be the optimal solution for the present in the choice of follow-up immunization strategies

Mucosal vaccines activate immune cells in the mucosal tissues of the nose and respiratory tract, acting as sentinels

Mucosal vaccines linked to "anti-infection"

On the evening of September 4, CanSino Bio issued an announcement that the recombinant new crown vaccine (type 5 adenovirus vector) developed by the company was included in emergency use

Inhaled Ad5-nCoV is the same as the previously approved adenoviral vector vaccine Ad5-nCoV from Cansino, but with a new aerosol inhalation method

In May, Lancet Respiratory Disease released the results of a clinical trial of the vaccine, which included 420 adults over the age of 18 who had completed two doses of the inactivated vaccine CoronaVac in
the past 3-9 months.

In this trial, 140 people were again vaccinated with 0.
1 ml of inhaled Ad5-nCoV, 140 people were vaccinated with 0.
2 ml, and another 140 people continued to use inactivated vaccines
.
The results showed that after 28 days of
inoculation, the neutralizing antibody GMT value of the 0.
1 ml group was 1937 for the original strain, and the 0.
2 ml group was 1351, compared with only 73.
5 (26 times and 18 times) for the homologous inactivated vaccine strengthening group;
after 28 days of inoculation, for the Delta variant strain, Heterologous inhalation Ad5-nCoV triggers neutralizing antibody levels that are about 3 times higher than the WHO international standard, while inactivated vaccine homologous vaccination is less than 20% of the international standard;
In addition to humoral immunity, the researchers say that inhaled Ad5-nCoV will induce a stronger cellular immune response compared to homologous boosting
.
Pictured: After the third injection, for the neutralizing antibody levels of wild-type SARS-CoV-2, blue, green and red corresponded to 0.
1 ml, 0.
2 ml and inactivated vaccine groups
, respectively.
Nature reported that the trial measured serum neutral antibody levels after vaccination and compared them horizontally with existing vaccines, and the positive results were the basis for confirming the efficacy of
inhaled AD5-nCoV.
But a series of clinical trials have not published detailed mucosal immunity data for the vaccine – its level is linked to
the ability to "prevent infection".
Another question is that although many teams around the world are currently testing the mucosal immune response of the respiratory tract, including secretory IgA (SIgA) antibodies, tissue-resident memory T cell levels, etc.
, to what extent can the new crown virus infection and transmission be prevented? There are currently no exact indicators
.
Zhuang Shilihe, a master of neuroscience at Hokkaido University, said in a post on Weibo that it is a good thing to be approved urgently, which is equivalent to an extra "shield", but the embarrassment is that mucosal immunity is the biggest advantage of inhaled vaccines compared to other vaccines, but there is currently a lack of direct research evidence
.

Are mucosal vaccines superior to traditional vaccines?
Professor Jin Dongyan of the School of Biomedical Sciences of the University of Hong Kong analyzed the "medical community" that due to the convenience of administration, high safety, and induced respiratory mucosal immunity, even if there is a lack of accurate data, inhaled Ad5-nCoV may have a certain breakthrough
in the prevention of infection.
With the "breakthrough infection" of the new crown virus becoming the norm, the research and development of mucosal new crown vaccines has long received attention
from the academic community.

Currently, about 100 mucosal COVID-19 vaccines are in
development worldwide.
"However, according to the past law of mucosal vaccines, the humoral and cellular immune response of the whole body is often inferior to that of the same type of intramuscular vaccine, which means that once infected, inhaled Ad5-nCoV is not necessarily better than the previous intramuscular Ad5-nCoV
in the prevention of severe disease.
" Jin Dongyan believes that the optimal immunization strategy is to first receive two more powerful intramuscular new crown vaccines, and then add an inhalation type as a sequential vaccination to supplement mucosal immunity
.
A study showing that natural infection, intramuscular injection and nasal inhalation vaccine corresponding to the sIgA, IgG antibody level
virology expert Chang Rongshan also said that mucosal immunity is characterized by a relatively fast onset of action, but the overall protective effect is not as good as humoral immunity and cellular immunity
.
In addition, compared with the bivalent mRNA vaccine approved overseas, the latest inhaled Ad5-nCoV did not perform antigen updates
against the Opichron variant.
On July 28, the aforementioned clinical study was updated on the preprint platform, showing that although neutralizing antibodies against Omikejong BA.
1 could be detected within six months of heterologous inoculation, they were significantly lower
than the original strain.

"In the CoronaVac group, almost no participants detected neutralizing antibodies
against BA.
1 at any point in time.

The study said
.
Jin Dongyan believes that although the mucosal vaccine can theoretically induce the triple protection of mucosal, cellular and humoral immunity, at the moment when the Aomi Kerong variant is popular, its comprehensive protection effect has to wait for real-world research data
.
According to CanSino Biologics, it is still uncertain when the vaccine will be launched because additional administrative approval procedures are needed, and the sale of the vaccine still depends on the epidemic situation at home and abroad and the vaccination situation at
home and abroad.

When will the indigenous "Omi kerong" vaccine be available?
In terms of clinical trial data, another approved Livzon Group V-01 recombinant protein vaccine also reflects the advantages of sequential vaccination, and the results of the Phase III clinical study were published in "Emerging Microorganisms and Infections" in July this year, recruiting more than 10,000 participants who had received two doses of inactivated vaccines
.
In terms of vaccine efficacy, after the sequential vaccination of V-01, the effectiveness of preventing NEW CROWN infection was further increased by 47.
8%
compared with the two-shot inactivated vaccine.

In terms of immunogenicity, after 28 days of vaccination, the neutralizing antibody GMT value of the V-01 vaccine group against the original strain was about 1875, and the two-dose inactivated vaccine group was 195.
7, an increase of about 9.
6 times
.
In fact, relying on strict non-pharmacological interventions (NPIs) over the past two years, China has achieved extremely low COVID-19 infection and mortality rates, but the level of herd immunity obtained by passive natural infections is therefore much lower than overseas
.

On the other hand, despite a vaccination rate of 90%, the decline in vaccine efficacy cannot be avoided
over time and strain mutation.
The newly approved two vaccines as "emergency use of reinforcing needles" also suggests a possible optimal solution for subsequent indigenous vaccination strategies, that is, the use of new crown vaccines for sequential vaccination
.

In June this year, Zhong Nanshan, an academician of the Chinese Academy of Engineering, publicly stated:
"Strengthen immunity with the same vaccine, and the effect of preventing infection is poor; With xenophic vaccines plus exemption, on the basis of two inactivated vaccines with subprotein vaccines or adenovirus vaccines or mRNA vaccines, the effect is significantly improved, and it is recommended to use xenophages as a sequential vaccination
.

"
From real-world data analysis, another recombinant protein vaccine ZF2001, which may be the most promising local COVID-19 vaccine at present, was jointly developed by the team of academician Gao Fu of the Institute of Microbiology of the Chinese Academy of Sciences and the subsidiary of Zhifei Biology, and was approved for sequential strengthening vaccination in February this year, and was further approved for listing
in March.
On May 4, the results of the Phase III clinical trial of ZF 2001 topped the New England Journal of Medicine, which included nearly 30,000 subjects, showing an average of 81.
4% protective efficacy against symptomatic COVID-19 infection within an average of two months after three injections, compared with 75.
7%
half a year later.

(Trial period is from December 2020 to December 2021)
And in addition to sequential vaccination, the development of monovalent and multivalent COVID-19 vaccines containing the Semicon variant may be more important
due to the large changes in the immune escape characteristics of the Omilon spectrum.

At present, 9 new crown vaccines in China have been approved for conditional marketing or emergency use, but none of them are specifically aimed at Omilon
.
It is reported that at present, a number of technical routes have carried out the research and development
of monovalent and multivalent Omiljung mutant vaccines.

After being approved for emergency use, Livzon Group recently issued an announcement that the company has developed a variety of mutant vaccines including Beta, Delta, Omicron and related divalent vaccines, which are being carried out simultaneouslyRelevant preclinical studies and clinical declarations
.
According to the "Science and Technology Daily" reported on September 5, the reporter learned from Kexing Company that the Chilean Institute of Public Health has approved a clinical study
evaluating the inactivated vaccine of Kexing trivalent new crown (prototype strain, Delta strain, Ormicron strain) and the monovalent Olmicoron strain inactivated vaccine.
Source: Medical Proofreader: Zang Hengjia
Editor: Tian Dongliang
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