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Overview of adenovirus vector COVID-19 vaccines
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Overview of adenovirus vector COVID-19 vaccines
Adenovirus ( Adenovirus , Ad ) vectors in the past been used in vaccines against other viruses, especially HIV and the Ebola virus, but not large-scale production, distribution or for use in humans.
Studies have tested several different serotypes of Ad encoding SARS-CoV-2 S protein and found that it is effective against COVID-19 .
Most COVID-19 vaccines focus on triggering an immune response (especially binding and neutralizing antibodies) against the S protein of SARS-CoV-2 .
S protein is a homotrimeric protein on the surface of virus particles, which is responsible for binding to the receptor angiotensin-converting enzyme 2 (ACE2) present on the plasma membrane of host cells to promote virus entry and infection.
Antibodies that bind to the S protein and prevent ACE2 from participating can neutralize SARS-CoV-2 and protect the host; non-neutralizing antibody responses can protect the host by promoting immune control and clearing the virus; virus-specific CD8 + T cells can eliminate infected Cells and inhibit virus replication.
Therefore, vaccines containing S protein can prevent COVID-19 infection.
Previous vaccines are usually formed by inactivating or attenuating pathogens or protein subunits. Years of research on next-generation vaccine platforms for existing and emerging diseases have promoted the development of nucleic acid and viral vectors as vaccine platforms.
By exchanging target coding genes, one pathogen can be adapted to another. This gene-based vaccine is critical to vaccine development for the COVID-19 pandemic.
History of adenovirus vectors
Ad is an unenveloped double-stranded DNA virus. Its icosahedral capsid diameter is between 80 and 100 nanometers. It was first discovered in the 1950s . There are more than 100 human serotypes. Its genome has been sequenced and assembled and assembled. The mechanism of replication is quite clear.
Ad can infect a variety of cells, including epithelial cells and endothelial cells, as well as hepatocytes and myoblasts. Ad in the 20 century 90 for gene expression vector for gene delivery in vivo treatment years, for the treatment of [alpha] -1 antitrypsin deficiency and cystic fibrosis. However, even if the Ad platform can reliably deliver the target gene, the vector also triggers an immune response, thereby inhibiting the long-term expression of the therapeutic gene.
Ad vector has a high degree of immunogenicity. After being introduced into the host, it can trigger an inherent inflammatory response, leading to an adaptive immune response to the Ad capsid. Although this immunogenicity limits the potential of Ad vectors for gene therapy, it is still attractive for vaccine platforms.
The short-term expression of foreign genes and the inherent immunogenicity of Ad virus particles make Ad a promising vaccine platform. Unlike many other protein or subunit vaccines, it does not require additional adjuvants.
Ad vector has been studied as a vaccine platform for many different viruses, including HIV , Ebola, Zika virus and SARS-CoV-2 . These vaccines use different Ad serotypes, from human Ad5 to human Ad26 , to chimpanzee Ads (ChAds) or rhesus Ads (RhAds) . Some of these experimental vaccines have been authorized for emergency use in Ebola and SARS-CoV-2 .
Ad vector vaccines use the inherent infectiousness of Ad to promote the expression of target vaccine antigens in vivo. This is achieved by deleting key viral replication genes (especially the E1 and E3 boxes) and inserting the coding sequence of the vaccine antigen, so that the vector cannot replicate while maintaining the original size of the genome (Figure 1 ).
The Ad vector vaccine induces an innate immune response parallel to the expression of the vaccine antigen, leading to the response of adaptive T cells and B cells to the Ad vector itself and the vaccine antigen. The innate response is mainly driven by the cytosolic DNA sensor that recognizes the Ad genome in the host cell , such as Toll -like receptor 9 ( TLR9 ) and cyclic guanosine phosphate AMP synthase ( cGAS ); the inherent response induced by empty Ad capsids is significantly higher than Low.
These sensors can trigger an inflammatory cascade, including the production of interferon ( IFN ) and other cytokines, and the recruitment of immune cells to the site of administration. Macrophages and dendritic cells ( DC) Are the first recruited cells that can absorb virus particles, and then express the vaccine transgene locally and after transport to the draining lymph nodes.
This expression and release in lymph nodes and the uptake of locally expressed antigens after lymphatic drainage can produce a strong adaptive immune response. Homologous T cells and B cells are activated by DCs in the lymph nodes ; CD8 + T cells are activated, they can be excreted from the lymph nodes, reach the site of infection, and kill the infected cells.
Naïve B cells produce the initial low-affinity antibodies, and also enter the germinal center ( GC ) reaction, the affinity matures and finally produces high-affinity antibodies.
The memory B cells that recognize the antigen may also proliferate and differentiate into antibody-secreting cells. This process is not only for the Ad vector itself, but also for the vaccine antigen encoded in the vector.
Figure 1 Adenovirus vector vaccine development process
Anti-vector immunization may pose a challenge to Ad vaccine strategy. About Ad most of the initial work has focused on vector Ad5 on, Ad5 is a clear and highly popular feature of Ad . Given the ubiquity of Ad5 in humans, most people have circulating anti- Ad5 antibodies.
High-titer antibodies against the serotype of the vector used can reduce the infectivity of the viral vector, thereby weakening the expression of the vaccine transgene and the required anti-vaccine immune response.
Although Ad5 vectors are still being used , one of the main strategies to circumvent pre-existing immune problems is to use rare Ad serotypes or non-human Ad .
A lot of work has been carried out in this field to determine the seroprevalence and immunogenicity of various Ads as carriers, and Ad26 has become a promising candidate.
At the same time, there is work to characterize and vectorize the Ads of non-human primates (including CHAD and RHAD ) that humans have little or no contact with before .
Given its modular nature, the Ad vaccine platform can be easily adapted to include almost any antigen of interest. Facts have proved that this is essential for rapid vaccine development in response to the SARS-CoV-2 and COVID-19 pandemics.
S protein subtypes in vaccines
Each COVID-19 vaccine based on Ad vector (US Food and Drug Administration ( FDA ), European Medicines Agency ( EMA ), China National Medical Products Administration, Russian Ministry of Health and / or World Health Organization ( WHO ) has Conditions approved) are composed of an incompletely replicated Ad vector encoding the full – length spike protein of SARS-CoV-2 (Table 1 ).
The Ad26.COV2.S vaccine produced by Janssen/Johnson&Johnson ( JnJ ) includes two proline mutations, which can stabilize the S protein and delete the furin cleavage site.
AstraZeneca’s ChAdOx1 nCoV-19 vaccine and CanSino ’s Ad5nCoV vaccine contain a tissue plasminogen activation ( tPA ) leader sequence before the S protein sequence. Gam-CoV-Vac vaccine code from Gamaleya InstituteSARS-CoV-2 S protein, which was sequenced and reported for the first time in January 2020 .
Table 1 Antigens and protocols of approved adenovirus vector COVID-19 vaccine
These Ad vector-based vaccines have been evaluated in preclinical and clinical studies. Preclinical models include NHP , usually rhesus monkeys, mice, ferrets, and Syrian golden hamsters. NHP is the preferred preclinical model for vaccine development because they reproduce the human immune response, and because SARS-CoV-2 is infected and infected in the upper respiratory tract (nose, mouth, throat, etc.) and lower respiratory tract (bronchi and lung) of NHP . Copying is the same as in humans. However, NHP usually only develops into a mild disease when it is infected with SARS-CoV-2 .
Hamsters can be used as models for protection research because they can develop into serious clinical diseases, including weight loss, pneumonia, and SARS-CoV-2 replication in various tissues including the upper and lower respiratory tracts.
Ferrets are a small animal model widely used in respiratory virus research because infected ferrets can cough and spread virus particles to other ferrets. The SARS-CoV-2 infection in ferrets is limited to the upper respiratory tract, and there is almost no virus in the lungs.
In addition, although their body temperature does rise, ferrets do not lose weight due to infection. Mice cannot be infected with SARS-CoV-2 naturally , but transgenic mice expressing human ACE2 (hACE2) can be infected, and wild-type mice can be infected with SARS-CoV-2 strains adapted to mice .
hACE2 transgenic mice are infected with SARS-CoV-2After weight loss and high levels of virus replication in the lower respiratory tract (lungs). Mouse-adapted SARS-CoV-2 can replicate in the upper and lower respiratory tracts of wild-type BALB/c mice, and can cause more serious diseases in elderly mice, which is closer to the human clinical phenotype of COVID-19 . These models all provide important insights into the immunogenicity and protective capabilities of vaccine candidates that are still in the preclinical stage.
Ad26.COV2.S vaccine (Janssen/Johnson & Johnson)
A single dose of Ad26.COV2.S vaccine from JnJ can protect rhesus monkeys from SARS-CoV-2 infection 6 weeks after vaccination . The clinical candidate vaccine is one of the seven candidate Ad26 vaccines tested in this study .
Each vaccine expresses a different SARS-CoV-2 S protein subtype. The vector expressing the full-length, double-proline stable, furin cleavage site of the S protein is the most immunogenic and effective.
Ad26.COV2.S vaccine can induce a strong humoral response 4 weeks after vaccination , including S protein receptor binding domain ( RBD ) binding antibodies, pseudovirus and live virus neutralizing antibodies, and IFNγ+CD8+ and CD4+ T cell responses.
By measuring the level of viral subgenomic mRNA ( sgRNA ) (indicating virus replication) to determine the protective effect, Ad26.COV2.S vaccine provides complete protection to the lungs and almost complete protection to the upper respiratory tract.
The Ad26.COV2.S vaccine was also tested in a hamster model, which mainly relies on measuring tissue weight loss and sgRNA to determine the vaccine ‘s ability to protect against clinical manifestations of severe SARS-CoV-2 infection.
The hamsters vaccinated with Ad26.COV2.S did not die except for slight weight loss and pneumonia, while the unvaccinated control group showed severe weight loss, pneumonia and some deaths.
The combination of these NHP and hamster data forms the preclinical basis for Ad26.COV2.S to enter clinical trials , and has been conditionally approved by the FDA , EMA , WHO and other regulatory agencies. Ongoing preclinical studies have proven the effectiveness of Ad26.COV2.S against SARS-CoV-2 variants in NHPs , especially B.1.351 ( β ).
ChAdOx1nCoV-19 ( AstraZeneca )
ChAdOx1 is ChAdY25 replication defective vector version, ChAdY25 is first isolated from chimpanzee feces samples of non-human Ad . Since ChAdY25 does not regularly infect humans, the pre-existing immunity to this vector is very low.
ChAdOx1 nCoV-19 vaccine encoding a fusion to full-length SARS-CoV-2 S sequence of a codon-optimized version of the 5 ‘ end of the tPA leader sequence. According to reports, ChAdOx1.
19-nCoV highly immunogenic in mice can be induced SARS-CoV-2 S binding antibodies and live virus neutralizing antibodies and antigen-specific IFNγ of CD8 + and CD4 + T cells.
Another preprint report stated that intranasal administration of ChAdOx1 nCoV-19 by NHP can also prevent pneumonia, but does not reduce the shedding of the D614G variant of SARS-CoV-2 .
In addition to mice and NHP , the ChAdOx1 nCoV-19 vaccine has also been tested in ferrets. According to reports, in ferrets, the vaccine can induce neutralizing antibodies against the original Wuhan – Hu -1 strain of SARS-CoV-2 and the D614G variant, and reduce the shedding of SARS-CoV-2 virus after the challenge .
Although the ChAdOx1 nCoV-19 single-dose intramuscular ( IM ) vaccine is sufficient to partially protect NHP and ferrets, the prime boost program induced a significantly stronger humoral immune response. This program was injected 28 days after the two injections. Currently , EMA , Conditional approval by WHO and other regulatory agencies.
The Ad5-nCoV vaccine is similar to the ChAdOx1 nCoV-19 vaccine, encoding a full-length mammalian expression codon-optimized S with a tPA signal peptide .
It is reported that the vaccine by IM and intranasally ( the IN ) administered mice induced a strong S -specific antibody binding and neutralizing antibodies by IM generated in mice induced by administration of IFN- [gamma] , TNF [alpha] or IL-2 in CD8 + T cells.
Assessed 3 or 5 days after infection, the lungs of IM and IN- administered mice were completely protected from the SARS-CoV-2 adapted to the mice . The turbinates of the mice in the IN group were completely protected, while the IM group was only partially protected.
In ferrets, Ad5-nCoV vaccine has similar immunogenicity through IM or IN administration, and is affected by SARS-CoV-2.Virus attack produces complete ( IN ) or partial ( IM ) upper respiratory tract protection. Both the IN and IM versions of the vaccine are in clinical trials.
Gam-COVID-Vac or Sputnik V (Gamaleya Research Institute)
The Gam-COVID-Vac vaccine, also known as Sputnik V , is a two-dose regimen of two different non-repetitive Ad vectors ( Ad26 and Ad5 ), each of which encodes the full-length S gene of SARS-CoV-2 .
Previous studies in the NHP have shown that Ad26 can induce a multifunctional cellular immune response, and subsequent Ad5 immunization can enhance the multifunctional cellular immune response.
Gam-COVID-Vac vaccine has not yet published preclinical data, although clinical studies refer to unpublished preclinical data in NHP and hamsters (including induction of cellular and humoral immune responses, protection of NHPs from infection, and immunosuppression of hamsters from SARS-CoV -2 death due to infection).
These data support the clinical doses of the first human trials and later trials, and have been conditionally approved by the Russian Ministry of Health.
Phase I/II : Safety and immunogenicity test
Each of the Ad vector vaccines discussed here has been evaluated in the first human trial ( Phase I/II ) to evaluate its safety, dosage, and immunogenicity.
Ad26.COV2.S( Janssen/Johnson & Johnson)
In September 2020 , Ad26.COV2.S was reported to be safe and immunogenic. The phase I/II trial tested the two doses of 1×10 11 and 5×10 10 virus particles ( VP ) in healthy people aged 18-55 and over 65 , respectively, with a single or two injections of the vaccine, and in 8 enhanced weeks. In these two cohorts, the vaccine was found to induce specific binding and neutralizing antibodies on day 29 after the initial dose , and antigen-specific CD8+ and Th1 CD4+ T cells on day 15 after vaccination .
Among the 25 participants in the 18-55 -year-old cohort, S antibodies and RBD- binding antibodies were detected in the vaccinated as early as the 8th day after vaccination , and then neutralizing antibodies were detected on the 15th day.
These antibodies show versatility through antibody-dependent complement deposition ( ADCD ), antibody-dependent neutrophil phagocytosis ( ADNP ), antibody-dependent cellular phagocytosis ( ADCP ) and antibody-dependent natural killer cell activation ( ADNKA ). Vaccines It continues to be effective for at least 71 days after vaccination .
In addition, the Ad26 vector induced neutralizing antibodies against itself in most of the subjects administered once and in all subjects administered twice. These data laid the foundation for the Phase III trial to evaluate the efficacy of the 5×10 10 VP dose (because the regimen is highly immunogenic, and the difference observed in the high-dose or enhanced group is minimal).
ChAdOx1 nCoV-19 (AstraZeneca)
Various dosage regimens of ChAdOx1 nCoV-19 vaccine have been studied. The first reported phase I/II trial focused on a single dose of 5×10 10 VP or the second dose ( 5×10 10 VP ) on the 28th day after the initial vaccination .
By day 14 , all subjects had produced S- binding antibodies and virus neutralizing antibodies; the neutralizing antibody titer of the single injection group had been increasing until the 56th day ; the primary vaccination – enhanced group reached the 35th day Peak.
These antibody responses include antibody-dependent neutrophil / monocyte phagocytosis ( ADNP , ADCP ), ADCD and ADNKA ; these Fc- mediated functions were significantly enhanced in the boost group. These two regimens also induced a strong cellular response, which was studied in detail in the single-dose group. The cell response after a single dose has a Th1 bias in the CD4+T cell compartment , and also includes a strong cytotoxic CD8+TCellular response. These include data demonstrating the improvement of the antibody response after the boost, and form the basis of a phase III trial evaluating the efficacy of two doses of ChAdOX1 nCoV-19 .
The Ad5 nCoV dose escalation phase I trial tested three doses ( 5×10 10 , 1×10 11 and 1.5×10 11 VP ) in 18-60 year old participants, and the results showed that the vaccine induced RBD binding, SARS -CoV-2 neutralizing antibodies and specifically produce IFNγ in T cells. Compared with patients with a pre-existing Ad5 neutralization titer ≤ 1:200 , patients with a pre-existing Ad5 neutralization titer ≥ 1:200 had a lower average response.
A phase II trial with more participants further tested the immunogenicity and safety of doses of 5×10 10 VP and 1×10 11 VP , both of which had lower reactogenicity in the phase I trial 1.5×10 11VP dosage. By day 28 after vaccination , these two doses induced a comparable level of humoral response to RBD , pseudovirus neutralization, and S- specific IFNγ to produce T cell responses, and regardless of the pre-existing Ad5 neutralization titer, both This result can be observed. The dose of 5×10 10 VP was less reactive than the dose of 1×10 11 VP , and the immunogenicity was almost the same, so it entered the phase III efficacy trial.
Gam-COVID-Vac (Gamaleya Research Institute)
Phase I/II trials studied a heterogeneous prime-boost regimen consisting of Ad26 and Ad5 doses to determine the best time for the second dose and the order of administration of two different doses. Binding antibodies and neutralizing antibodies were detected in the participants 14 days after vaccination .
In the single-dose cohort (with only one injection of Ad26 or Ad5 ) 21 days after vaccination and the enhanced cohort at least 42 days after the first vaccination , the antibody titer continued to rise .
Compared with the double-dose regimen, the single-dose regimen caused weaker cell response, lower levels of antigen-specific CD8+ and CD4+ T cell proliferation and IFNγ release. Frozen vaccines and freeze-dried vaccines performed similarly in each subgroup. III trials program comprises . 1 × 10 . 11 VP dose Ad26 vector -S and 21 days . 1 × 10 . 11 VP dose of Ad5 vector -S .
The third stage: safety and effectiveness test
Table 2 summarizes the reported efficacy of each Ad vector vaccine.
Table 2 Efficacy and approval status of adenovirus-mediated COVID-19 vaccine
Ad26.COV2.S( Johnson & Johnson)
JnJ ‘s Phase III trial for Ad26.COV2.S included more than 44,000 participants from Argentina, Brazil, Chile, Colombia, Mexico, Peru, South Africa and the United States . Participants randomly received 5×10 10 VP Ad26.COV2.S or placebo at a ratio of 1:1 in a double-blind manner .
The primary endpoint of the study is the effectiveness of moderate to severe COVID-19 at least 14 days and 28 days after immunization . A single injection of Ad26.COV2.S vaccine at least 28 days after vaccination, the effective rate of preventing moderate to severe COVID-19 at all test sites is 66.1% .
According to reports, the vaccine has an effective rate of 72% in the United States , 68% in Brazil , and 64% in South Africa . 95% of the virus has been identified as the B.1.351 ( β ) variant. The vaccine provided 85% protection from severe diseases and100% hospitalization and death protection.
AstraZeneca’s ChAdOx1 nCoV-19 Phase III trial was conducted in the United Kingdom, Brazil and South Africa. More than 23,000 participants were blinded and randomly received ChAdOx1 nCoV-19 vaccine or placebo at a 1:1 ratio , at least 28 days apart . The main analysis evaluated the symptomatic COVID-19 in patients more than 14 days after the second dose .
According to reports, the efficacy of patients who received two standard doses was 62.1% , while the efficacy of patients who received the standard dose after the low dose in the United Kingdom was higher. This may be due to the difference in the interval between the two doses.
In a small study in South Africa, it was found that the efficacy of B.1.351 ( β ) variants was negligible, while a study in the United Kingdom observed that the efficacy of B.1.1.7 ( α ) variants was 70.4% .
According to a double-blind study ( NCT04526990 ) conducted in Argentina, Chile, Mexico, Pakistan and the Russian Federation , CanSino reported that its Ad5 nCoV vaccine is 65.7% effective for symptomatic COVID-19 .
Approximately 30,000 participants were randomly assigned to the treatment group or the control group at a ratio of 1:1 . The primary endpoint of the assessment is the incidence of PCR- positive COVID-19 cases and the incidence of serious adverse events at least 28 days after vaccination .
Gam-COVID-Vac (Gamaleya Research Institute)
The Gam-COVID-Vac vaccine was tested in a double-blind phase III study in 25 locations in Russia . Nearly 22,000 participants were recruited and randomly received two doses of vaccine or placebo at a ratio of 3:1 . The main result is the incidence of PCR- positive COVID-19 cases at least 21 days after the first dose of vaccine , and the reported efficacy is 91.6% .
In the phase III trial, all vaccines were reported to be safe. After the launch of the vaccine, the AstraZeneca and JnJ vaccines are associated with rare cases of thrombosis and thrombocytopenia syndrome ( TTS ), also known as vaccine-induced immune thrombotic thrombocytopenia ( VITT ), similar to autoimmune heparin Induced thrombocytopenia and antiplatelet factor 4 antibodies.
These rare events have caused warnings, and preclinical and clinical studies are currently underway to better understand and avoid these reactions. A case of Moderna mRNA vaccine meeting the definition of TTS/VITT was also reported recently ; AstraZeneca and JnJ vaccines are also associated with rare cases of Guillain – Barré syndrome.
Although the coronavirus has a copying RNA proofreading mechanism, it does undergo mutations, including in mutants, to escape host immune pressure. Since the number of SARS-CoV-2 infections has been extremely high since the end of 2019 , the emergence of SARS-CoV-2 variants is not surprising.
The mutations of S and other viral proteins are related to SARS COV-2 related variants and variants of interest ( VOC ). Because of the way these mutations change S , they can increase their affinity for ACE2 through infection or vaccination , and reduce their affinity for antibodies against the original Wuhan- Hu-1 S , because the vaccines tested and approved so far are based on the original S .
These changes include, for example, a charge or addition of a switch (e.g., B.1.351 and P.1 variant E484K or B.1.617 variant L452R ) or addition of a large aromatic side chains (e.g., B.1.1.7 , B .1.351 and P.1 variants of N501Y), eliminating the binding of antibodies that cannot adapt to these significant changes in the paratope.
Many reports indicate that certain VOCs , namely B.1.351 ( β ), P.1 ( γ ), and B.1.617.2 ( δ ), have a lower ability to neutralize and bind to the serum of vaccinated individuals in vitro. Not close. Some III trial site is located VOC high incidence areas, these experiments (e.g., South Africa Ad26.COV2.S and ChAdOx1 nCoV-19 Test) help explore the expression of Wuhan -Hu-1 or WA1 / 2020 strain S in The effectiveness of the vaccine on VOC .
In South Africa, where there are many B.1.351 ( β ) variants, Ad26.COV2.S has an effective rate of 64% for mild and moderate diseases and 82% for severe diseases . VOC has triggered the development and production of various vaccines currently in use.
The COVID-19 pandemic has caused the fastest vaccine development in history, and millions of people have now been vaccinated with Ad vector vaccines. Past clinical trials of Ad vaccines reported that the antibody response lasted for at least one year.
According to reports, the Ad26.COV2.S vaccine from JnJ has cell and humoral response durability for up to 8 months, including B.1.351 ( β ) and B.1.617.2 ( δ ) over time. The breadth of neutralizing antibodies of the included variants is increased. About COVID-19 vaccine response Persistence of the latest information will continue to occur in real time.
Ad vector vaccines play an important role in global vaccine work against COVID-19 . The highly immunogenic, easily adaptable and easy-to-manufacture Ad vector has proven to be very suitable for pandemic response: four Ad- based vaccines were approved by regulatory authorities within about one year after the SARS-CoV-2 sequence was published .
Ad26.COV2.S , ChAdOx1-nCov-19 , Ad5-nCov and Gam-COVID-Vac vaccines have been shown to have protective effects against symptomatic COVID-19 disease in humans . Academia and industry are continuing to conduct clinical research on other Ad vector vaccines against SARS-CoV-2 . In the future, Ad vaccines against multiple pathogens may also be developed .
Reference source: Catherine Jacob-Dolan and Dan H. Barouch. COVID-19 Vaccines: Adenoviral Vectors.Annual Review of Medicine
Overview of adenovirus vector COVID-19 vaccines
(source:internet, reference only)