新型冠状病毒亚单位疫苗研究进展及现状*

[3]

Doherty

M

, Schmidt-Ott

R

, Santos

J I

, et al.

Vaccination of special populations: protecting the vulnerable

Vaccine, 2016, 34(52): 6681-6690.

PMID:27876197 [本文引用: 1]

One of the strategic objectives of the 2011-2020 Global Vaccine Action Plan is for the benefits of immunisation to be equitably extended to all people. This approach encompasses special groups at increased risk of vaccine-preventable diseases, such as preterm infants and pregnant women, as well as those with chronic and immune-compromising medical conditions or at increased risk of disease due to immunosenescence. Despite demonstrations of effectiveness and safety, vaccine uptake in these special groups is frequently lower than expected, even in developed countries with vaccination strategies in place. For example, uptake of the influenza vaccine in pregnancy rarely exceeds 50% in developed countries and, although data are scarce, it appears that only half of preterm infants are up-to-date with routine paediatric vaccinations. Many people with chronic medical conditions or who are immunocompromised due to disease or aging are also under-vaccinated. In the US, coverage among people aged 65years or older was 67% for the influenza vaccine in the 2014-2015 season and 55-60% for tetanus and pneumococcal vaccines in 2013, while the coverage rate for herpes zoster vaccination among those aged 60years or older was only 24%. In most other countries, rates are far lower. Reasons for under-vaccination of special groups include fear of adverse outcomes or illness caused by the vaccine, the inconvenience (and in some settings, cost) of vaccination and lack of awareness of the need for vaccination or national recommendations. There is also evidence that healthcare providers' attitudes towards vaccination are among the most important influences on the decision to vaccinate. It is clear that physicians' adherence to recommendations needs to be improved, particularly where patients receive care from multiple subspecialists and receive little or no care from primary care providers.Copyright Â© 2016. Published by Elsevier Ltd.

[4]

Lee

A R Y B

, Wong

S Y

, Chai

L Y A

, et al.

Efficacy of COVID-19 vaccines in immunocompromised patients: systematic review and meta-analysis

BMJ (Clinical Research Ed), 2022, 376: e068632.

[5]

Cui

J

, Li

F

, Shi

Z L

.

Origin and evolution of pathogenic coronaviruses

Nature Reviews Microbiology, 2019, 17 (3): 181-192.

[6]

Drosten

C

, Günther

S

, Preiser

W

, et al.

Identification of a novel coronavirus in patients with severe acute respiratory syndrome

The New England Journal of Medicine, 2003, 348(20): 1967-1976.

[7]

Zaki

A M

, van Boheemen

S

, Bestebroer

T M

, et al.

Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia

The New England Journal of Medicine, 2012, 367(19): 1814-1820.

PMID:23075143 [本文引用: 1]

A previously unknown coronavirus was isolated from the sputum of a 60-year-old man who presented with acute pneumonia and subsequent renal failure with a fatal outcome in Saudi Arabia. The virus (called HCoV-EMC) replicated readily in cell culture, producing cytopathic effects of rounding, detachment, and syncytium formation. The virus represents a novel betacoronavirus species. The closest known relatives are bat coronaviruses HKU4 and HKU5. Here, the clinical data, virus isolation, and molecular identification are presented. The clinical picture was remarkably similar to that of the severe acute respiratory syndrome (SARS) outbreak in 2003 and reminds us that animal coronaviruses can cause severe disease in humans.

[8]

Zhou

P

, Yang

X L

, Wang

X G

, et al.

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Nature, 2020, 579 (7798): 270-273.

[9]

Yao

H P

, Song

Y T

, Chen

Y

, et al.

Molecular architecture of the SARS-CoV-2 virus

Cell, 2020, 183(3): 730-738.e13.

[10]

Hoffmann

M

, Kleine-Weber

H

, Schroeder

S

, et al.

SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor

Cell, 2020, 181(2): 271-280.e8.

PMID:32142651 [本文引用: 1]

The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.Copyright © 2020 Elsevier Inc. All rights reserved.

[11]

Wrapp

D

, Wang

N S

, Corbett

K S

, et al.

Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

Science, 2020, 367(6483): 1260-1263.

[12]

Lan

J

, Ge

J

, Yu

J

, et al.

Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE2 receptor

Nature, 2020, 581 (7807): 215-220.

[13]

Shang

J

, Ye

G

, Shi

K

, et al.

Structural basis of receptor recognition by SARS-CoV-2

Nature, 2020, 581 (7807): 221-224.

[14]

Wang

Q H

, Zhang

Y F

, Wu

L L

, et al.

Structural and functional basis of SARS-CoV-2 entry by using human ACE2

Cell, 2020, 181(4): 894-904.e9.

[15]

Cai

Y F

, Zhang

J

, Xiao

T S

, et al.

Distinct conformational states of SARS-CoV-2 spike protein

Science, 2020, 369(6511): 1586-1592.

[16]

Ke

Z

, Oton

J

, Qu

K

, et al.

Structures and distributions of SARS-CoV-2 spike proteins on intact virions

Nature, 2020, 588 (7838): 498-502.

[17]

Lauring

A S

, Andino

R

.

Quasispecies theory and the behavior of RNA viruses

PLoS Pathogens, 2010, 6(7): e1001005.

[18]

Li

Q Q

, Wu

J J

, Nie

J H

, et al.

The impact of mutations in SARS-CoV-2 spike on viral infectivity and antigenicity

Cell, 2020, 182(5): 1284-1294.e9.

[19]

Volz

E

, Hill

V

, McCrone

J T

, et al.

Evaluating the effects of SARS-CoV-2 spike mutation D614G on transmissibility and pathogenicity

Cell, 2021, 184(1): 64-75.e11.

[20]

Garcia-Beltran

W F

, Lam

E C

, St

Denis K

, et al.

Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity

Cell, 2021, 184(9): 2372-2383.e9.

PMID:33743213 [本文引用: 1]

Vaccination elicits immune responses capable of potently neutralizing SARS-CoV-2. However, ongoing surveillance has revealed the emergence of variants harboring mutations in spike, the main target of neutralizing antibodies. To understand the impact of these variants, we evaluated the neutralization potency of 99 individuals that received one or two doses of either BNT162b2 or mRNA-1273 vaccines against pseudoviruses representing 10 globally circulating strains of SARS-CoV-2. Five of the 10 pseudoviruses, harboring receptor-binding domain mutations, including K417N/T, E484K, and N501Y, were highly resistant to neutralization. Cross-neutralization of B.1.351 variants was comparable to SARS-CoV and bat-derived WIV1-CoV, suggesting that a relatively small number of mutations can mediate potent escape from vaccine responses. While the clinical impact of neutralization resistance remains uncertain, these results highlight the potential for variants to escape from neutralizing humoral immunity and emphasize the need to develop broadly protective interventions against the evolving pandemic.Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.

[21]

Faria

N R

, Mellan

T A

, Whittaker

C

, et al.

Genomics and epidemiology of the P.1 SARS-CoV-2 lineage in Manaus, Brazil

Science, 2021, 372(6544): 815-821.

PMID:33853970 [本文引用: 1]

Cases of SARS-CoV-2 infection in Manaus, Brazil, resurged in late 2020, despite previously high levels of infection. Genome sequencing of viruses sampled in Manaus between November 2020 and January 2021 revealed the emergence and circulation of a novel SARS-CoV-2 variant of concern. Lineage P.1, acquired 17 mutations, including a trio in the spike protein (K417T, E484K and N501Y) associated with increased binding to the human ACE2 receptor. Molecular clock analysis shows that P.1 emergence occurred around mid-November 2020 and was preceded by a period of faster molecular evolution. Using a two-category dynamical model that integrates genomic and mortality data, we estimate that P.1 may be 1.7-2.4-fold more transmissible, and that previous (non-P.1) infection provides 54-79% of the protection against infection with P.1 that it provides against non-P.1 lineages. Enhanced global genomic surveillance of variants of concern, which may exhibit increased transmissibility and/or immune evasion, is critical to accelerate pandemic responsiveness.Copyright © 2021, American Association for the Advancement of Science.

[22]

Dhar

M S

, Marwal

R

, Vs

R

, et al.

Genomic characterization and epidemiology of an emerging SARS-CoV-2 variant in Delhi, India

Science, 2021, 374(6570): 995-999.

[23]

Tegally

H

, Wilkinson

E

, Lessells

R J

, et al.

Sixteen novel lineages of SARS-CoV-2 in South Africa

Nature Medicine, 2021, 27 (3): 440-446.

[24]

Yadav

P D

, Gupta

N

, Potdar

V

, et al.

Isolation and genomic characterization of SARS-CoV-2 Omicron variant obtained from human clinical specimens

Viruses, 2022, 14(3): 461.

[25]

Davies

N G

, Abbott

S

, Barnard

R C

, et al.

Estimated transmissibility and impact of SARS-CoV-2 lineage B.1.1.7 in England

Science, 2021, 372(6538): eabg3055.

[26]

Wang

P

, Nair

M S

, Liu

L

, et al.

Antibody resistance of SARS-CoV-2 variants B.1.351 and B.1.1.7

Nature, 2021, 593 (7857): 130-135.

[27]

Wang

P F

, Casner

R G

, Nair

M S

, et al.

Increased resistance of SARS-CoV-2 variant P.1 to antibody neutralization

Cell Host & Microbe, 2021, 29(5): 747-751.e4.

[28]

Li

B

, Deng

A

, Li

K

, et al.

Viral infection and transmission in a large, well-traced outbreak caused by the SARS-CoV-2 Delta variant

Nature Communications, 2022, 13: 460.

[29]

Cele

S

, Jackson

L

, Khoury

D S

, et al.

Omicron extensively but incompletely escapes Pfizer BNT162b2 neutralization

Nature, 2022, 602 (7898): 654-656.

[30]

Liu

L

, Iketani

S

, Guo

Y

, et al.

Striking antibody evasion manifested by the Omicron variant of SARS-CoV-2

Nature, 2022, 602 (7898): 676-681.

[31]

Ge

J

, Wang

R

, Ju

B

, et al.

Antibody neutralization of SARS-CoV-2 through ACE 2 receptor mimicry

Nature Communications, 2021, 12: 250.

[32]

Piccoli

L

, Park

Y J

, Tortorici

M A

, et al.

Mapping neutralizing and immunodominant sites on the SARS-CoV-2 spike receptor-binding domain by structure-guided high-resolution serology

Cell, 2020, 183(4): 1024-1042.e21.

PMID:32991844 [本文引用: 2]

Analysis of the specificity and kinetics of neutralizing antibodies (nAbs) elicited by SARS-CoV-2 infection is crucial for understanding immune protection and identifying targets for vaccine design. In a cohort of 647 SARS-CoV-2-infected subjects, we found that both the magnitude of Ab responses to SARS-CoV-2 spike (S) and nucleoprotein and nAb titers correlate with clinical scores. The receptor-binding domain (RBD) is immunodominant and the target of 90% of the neutralizing activity present in SARS-CoV-2 immune sera. Whereas overall RBD-specific serum IgG titers waned with a half-life of 49 days, nAb titers and avidity increased over time for some individuals, consistent with affinity maturation. We structurally defined an RBD antigenic map and serologically quantified serum Abs specific for distinct RBD epitopes leading to the identification of two major receptor-binding motif antigenic sites. Our results explain the immunodominance of the receptor-binding motif and will guide the design of COVID-19 vaccines and therapeutics.Copyright © 2020 Elsevier Inc. All rights reserved.

[33]

Barnes

C O

, West

A P Jr

, Huey-Tubman

K E

, et al.

Structures of human antibodies bound to SARS-CoV-2 spike reveal common epitopes and recurrent features of antibodies

Cell, 2020, 182(4): 828-842.e16.

[34]

Pallesen

J

, Wang

N S

, Corbett

K S

, et al.

Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen

Proceedings of the National Academy of Sciences of the United States of America, 2017, 114(35): E7348-E7357.

[35]

Chattopadhyay

S

, Chen

J Y

, Chen

H W

, et al.

Nanoparticle vaccines adopting virus-like features for enhanced immune potentiation

Nanotheranostics, 2017, 1(3): 244-260.

PMID:29071191 [本文引用: 1]

Synthetic nanoparticles play an increasingly significant role in vaccine design and development as many nanoparticle vaccines show improved safety and efficacy over conventional formulations. These nanoformulations are structurally similar to viruses, which are nanoscale pathogenic organisms that have served as a key selective pressure driving the evolution of our immune system. As a result, mechanisms behind the benefits of nanoparticle vaccines can often find analogue to the interaction dynamics between the immune system and viruses. This review covers the advances in vaccine nanotechnology with a perspective on the advantages of virus mimicry towards immune potentiation. It provides an overview to the different types of nanomaterials utilized for nanoparticle vaccine development, including functionalization strategies that bestow nanoparticles with virus-like features. As understanding of human immunity and vaccine mechanisms continue to evolve, recognizing the fundamental semblance between synthetic nanoparticles and viruses may offer an explanation for the superiority of nanoparticle vaccines over conventional vaccines and may spur new design rationales for future vaccine research. These nanoformulations are poised to provide solutions towards pressing and emerging human diseases.

[36]

Zhao

L

, Seth

A

, Wibowo

N

, et al.

Nanoparticle vaccines

Vaccine, 2014, 32(3): 327-337.

[37]

Ryzhikov

A B

, Ryzhikov

E А

, Bogryantseva

M P

, et al.

Immunogenicity and protectivity of the peptide candidate vaccine against SARS-CoV-2

Annals of the Russian Academy of Medical Sciences, 2021, 76(1): 5-19.

[38]

Casalino

L

, Gaieb

Z

, Goldsmith

J A

, et al.

Beyond shielding: the roles of glycans in the SARS-CoV-2 spike protein

ACS Central Science, 2020, 6(10): 1722-1734.

PMID:33140034 [本文引用: 1]

The ongoing COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in more than 28,000,000 infections and 900,000 deaths worldwide to date. Antibody development efforts mainly revolve around the extensively glycosylated SARS-CoV-2 spike (S) protein, which mediates host cell entry by binding to the angiotensin-converting enzyme 2 (ACE2). Similar to many other viral fusion proteins, the SARS-CoV-2 spike utilizes a glycan shield to thwart the host immune response. Here, we built a full-length model of the glycosylated SARS-CoV-2 S protein, both in the open and closed states, augmenting the available structural and biological data. Multiple microsecond-long, all-atom molecular dynamics simulations were used to provide an atomistic perspective on the roles of glycans and on the protein structure and dynamics. We reveal an essential structural role of -glycans at sites N165 and N234 in modulating the conformational dynamics of the spike's receptor binding domain (RBD), which is responsible for ACE2 recognition. This finding is corroborated by biolayer interferometry experiments, which show that deletion of these glycans through N165A and N234A mutations significantly reduces binding to ACE2 as a result of the RBD conformational shift toward the "down" state. Additionally, end-to-end accessibility analyses outline a complete overview of the vulnerabilities of the glycan shield of the SARS-CoV-2 S protein, which may be exploited in the therapeutic efforts targeting this molecular machine. Overall, this work presents hitherto unseen functional and structural insights into the SARS-CoV-2 S protein and its glycan coat, providing a strategy to control the conformational plasticity of the RBD that could be harnessed for vaccine development.

[39]

Walls

A C

, Tortorici

M A

, Frenz

B

, et al.

Glycan shield and epitope masking of a coronavirus spike protein observed by cryo-electron microscopy

Nature Structural & Molecular Biology, 2016, 23 (10): 899-905.

[40]

Walls

A C

, Xiong

X L

, Park

Y J

, et al.

Unexpected receptor functional mimicry elucidates activation of coronavirus fusion

Cell, 2019, 176(5): 1026-1039.e15.

[41]

Çelik

E

, Çalı

P

.

Production of recombinant proteins by yeast cells

Biotechnology Advances, 2012, 30(5): 1108-1118.

[42]

Shanmugaraj

B

, Bulaon

C J I

, Phoolcharoen

W

.

Plant molecular farming: a viable platform for recombinant biopharmaceutical production

Plants (Basel, Switzerland), 2020, 9(7): 842.

[43]

郝宇娉, 陆琳, 杨志红.

转基因植物疫苗的研究进展

核农学报, 2020, 34(12): 2708-2724.

Hao

Y P

, Lu

L

, Yang

Z H

.

Progress on transgenic plants vaccines

Journal of Nuclear Agricultural Sciences, 2020, 34(12): 2708-2724.

[44]

Luo

M

, Shao

B

, Yu

J Y

, et al.

Simultaneous enhancement of cellular and humoral immunity by the high salt formulation of Al(OH)3 adjuvant

Cell Research, 2017, 27 (4): 586-589.

[45]

张林焱, 周旭.

疫苗用氢氧化铝佐剂的研究现状

中国生物制品学杂志, 2020, 33(2): 213-215, 221.

Zhang

L Y

, Zhou

X

.

Research status of aluminum hydroxide adjuvant for vaccine

Chinese Journal of Biologicals, 2020, 33(2): 213-215, 221.

[46]

Bode

C

, Zhao

G

, Steinhagen

F

, et al.

CpG DNA as a vaccine adjuvant

Expert Review of Vaccines, 2011, 10(4): 499-511.

[47]

Gordon

D L

, Sajkov

D

, Honda-Okubo

Y

, et al.

Human phase 1 trial of low-dose inactivated seasonal influenza vaccine formulated with Advax? delta inulin adjuvant

Vaccine, 2016, 34(33): 3780-3786.

PMID:27342914 [本文引用: 1]

Influenza vaccines are usually non-adjuvanted but addition of adjuvant may improve immunogenicity and permit dose-sparing, critical for vaccine supply in the event of an influenza pandemic. The aim of this first-in-man study was to determine the effect of delta inulin adjuvant on the safety and immunogenicity of a reduced dose seasonal influenza vaccine. Healthy male and female adults aged 18-65years were recruited to participate in a randomized controlled study to compare the safety, tolerability and immunogenicity of a reduced-dose 2007 Southern Hemisphere trivalent inactivated influenza vaccine formulated with Advax™ delta inulin adjuvant (LTIV+Adj) when compared to a full-dose of the standard TIV vaccine which does not contain an adjuvant. LTIV+Adj provided equivalent immunogenicity to standard TIV vaccine as assessed by hemagglutination inhibition (HI) assays against each vaccine strain as well as against a number of heterosubtypic strains. HI responses were sustained at 3months post-immunisation in both groups. Antibody landscapes against a large panel of H3N2 influenza viruses showed distinct age effects whereby subjects over 40years old had a bimodal baseline HI distribution pattern, with the highest HI titers against the very oldest H3N2 isolates and with a second HI peak against influenza isolates from the last 5-10years. By contrast, subjects >40years had a unimodal baseline HI distribution with peak recognition of H3N2 isolates from approximately 20years ago. The reduced dose TIV vaccine containing Advax adjuvant was well tolerated and no safety issues were identified. Hence, delta inulin may be a useful adjuvant for use in seasonal or pandemic influenza vaccines. Australia New Zealand Clinical Trial Registry: ACTRN12607000599471.Copyright © 2016 Elsevier Ltd. All rights reserved.

[48]

Gordon

D

, Kelley

P

, Heinzel

S

, et al.

Immunogenicity and safety of Advax^TM, a novel polysaccharide adjuvant based on delta inulin, when formulated with hepatitis B surface antigen: a randomized controlled phase 1 study

Vaccine, 2014, 32(48): 6469-6477.

PMID:25267153 [本文引用: 1]

There is a need for additional safe and effective human vaccine adjuvants. Advax™ is a novel adjuvant produced from semi-crystalline particles of delta inulin. In animal studies Advax enhanced humoral and cellular immunity to hepatitis B surface antigen (HBsAg) without inducing local or systemic reactogenicity. This first-in-man Phase 1 clinical trial tested the safety and tolerability of three intramuscular doses of HBsAg formulated with Advax in a group of healthy adult subjects. Advax was well tolerated with injection site pain scores not significantly different to subjects receiving HBsAg alone and no adverse events were reported in subjects that received Advax. Seroprotection and HBsAb geometric mean titers (GMT) after three immunizations were higher in the Advax 5mg (seroprotection 5/6, 83.3%, GMT 40.7, 95% CI 11.9-139.1) and 10mg (seroprotection 4/5, 80%, GMT 51.6, 95% CI 10.0-266.2) groups versus HBsAg alone (seroprotection 1/5, 20%, GMT 4.1, 95% CI 1.3-12.8). Similarly the proportion of subjects with positive CD4 T-cell responses to HBsAg was higher in the Advax 5mg (4/6, 67%) and Advax 10mg (4/5, 80%) groups versus HBsAg alone (1/5, 20%). These results confirm the safety, tolerability and immunogenicity of Advax adjuvant observed in preclinical studies. Advax may represent a suitable replacement for alum adjuvants in prophylactic human vaccines subject to confirmation of current results in larger studies. Australia and New Zealand Clinical Trial Registry: ACTRN12607000598482. Copyright © 2014 Elsevier Ltd. All rights reserved.

[49]

Garçon

N

, Vaughn

D W

, Didierlaurent

A M

.

Development and evaluation of AS03, an adjuvant system containing α-tocopherol and squalene in an oil-in-water emulsion

Expert Review of Vaccines, 2012, 11(3): 349-366.

[50]

Cohet

C

, van der Most

R

, Bauchau

V

, et al.

Safety of AS03-adjuvanted influenza vaccines: a review of the evidence

Vaccine, 2019, 37(23): 3006-3021.

[51]

Black

S

, Della

Cioppa G

, Malfroot

A

, et al.

Safety of MF59-adjuvanted versus non-adjuvanted influenza vaccines in children and adolescents: an integrated analysis

Vaccine, 2010, 28(45): 7331-7336.

[52]

Bengtsson

K L

, Song

H F

, Stertman

L

, et al.

Matrix-M adjuvant enhances antibody, cellular and protective immune responses of a Zaire Ebola∕Makona virus glycoprotein (GP) nanoparticle vaccine in mice

Vaccine, 2016, 34(16): 1927-1935.

PMID:26921779 [本文引用: 1]

Ebola virus (EBOV) causes severe hemorrhagic fever for which there is no approved treatment or preventive vaccine. Immunological correlates of protective immunity against EBOV disease are not well understood. However, non-human primate studies have associated protection of experimental vaccines with binding and neutralizing antibodies to the EBOV glycoprotein (GP) as well as EBOV GP-specific CD4(+) and CD8(+) T cells. In this report a full length, unmodified Zaire EBOV GP gene from the 2014 EBOV Makona strain (EBOV/Mak) was cloned into a baculovirus vector. Recombinant EBOV/Mak GP was produced in Sf9 insect cells as glycosylated trimers and, when purified, formed spherical 30-40 nm particles. In mice, EBOV/Mak GP co-administered with the saponin adjuvant Matrix-M was significantly more immunogenic, as measured by virus neutralization titers and anti-EBOV/Mak GP IgG as compared to immunization with AlPO4 adjuvanted or non-adjuvanted EBOV/Mak GP. Similarly, antigen specific T cells secreting IFN-γ were induced most prominently by EBOV/Mak GP with Matrix-M. Matrix-M also enhanced the frequency of antigen-specific germinal center B cells and follicular helper T (TFH) cells in the spleen in a dose-dependent manner. Immunization with EBOV/Mak GP with Matrix-M was 100% protective in a lethal viral challenge murine model; whereas no protection was observed with the AlPO4 adjuvant and only 10% (1/10) mice were protected in the EBOV/Mak GP antigen alone group. Matrix-M adjuvanted vaccine induced a rapid onset of specific IgG and neutralizing antibodies, increased frequency of multifunctional CD4+ and CD8(+) T cells, specific TFH cells, germinal center B cells, and persistence of EBOV GP-specific plasma B cells in the bone marrow. Taken together, the addition of Matrix-M adjuvant to the EBOV/Mak GP nanoparticles enhanced both B and T-cell immune stimulation which may be critical for an Ebola subunit vaccine with broad and long lasting protective immunity.Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

[53]

Dai

L P

, Zheng

T Y

, Xu

K

, et al.

A universal design of Betacoronavirus vaccines against COVID-19, MERS, and SARS

Cell, 2020, 182(3): 722-733.e11.

[54]

AlKaabi

N

, Yang

Y K

, Zhang

J

, et al.

Safety and immunogenicity of a heterologous boost with a recombinant vaccine, NVSI-06-07, in the inactivated vaccine recipients from UAE: a phase 2 randomised, double-blinded, controlled clinical trial

medRxiv, 2022. DOI: 10.1101∕2021.12.29.21268499.

[55]

Liang

Y

, Zhang

J

, Yuan

R Y

, et al.

Design of a mutation-integrated trimeric RBD with broad protection against SARS-CoV-2

Cell Discovery, 2022, 8: 17.

PMID:35169113 [本文引用: 4]

The continuous emergence of SARS-CoV-2 variants highlights the need of developing vaccines with broad protection. Here, according to the immune-escape capability and evolutionary convergence, the representative SARS-CoV-2 strains carrying the hotspot mutations were selected. Then, guided by structural and computational analyses, we present a mutation-integrated trimeric form of spike receptor-binding domain (mutI-tri-RBD) as a broadly protective vaccine candidate, which combined heterologous RBDs from different representative strains into a hybrid immunogen and integrated immune-escape hotspots into a single antigen. When compared with a homo-tri-RBD vaccine candidate in the stage of phase II trial, of which all three RBDs are derived from the SARS-CoV-2 prototype strain, mutI-tri-RBD induced significantly higher neutralizing antibody titers against the Delta and Beta variants, and maintained a similar immune response against the prototype strain. Pseudo-virus neutralization assay demonstrated that mutI-tri-RBD also induced broadly strong neutralizing activities against all tested 23 SARS-CoV-2 variants. The in vivo protective capability of mutI-tri-RBD was further validated in hACE2-transgenic mice challenged by the live virus, and the results showed that mutI-tri-RBD provided potent protection not only against the SARS-CoV-2 prototype strain but also against the Delta and Beta variants.© 2022. The Author(s).

[56]

Sun

S

, Cai

Y

, Song

T Z

, et al.

Interferon-armed RBD dimer enhances the immunogenicity of RBD for sterilizing immunity against SARS-CoV-2

Cell Research, 2021, 31 (9): 1011-1023.

[57]

Toledo-Romani

M E

, Garcia-Carmenate

M

, Silva

C V

, et al.

Efficacy and safety of Soberana 02, a COVID-19 conjugate vaccine in heterologous three-dose combination

medRxiv, 2021. DOI: 10.1101∕2021.10.31.21265703.

[58]

Limonta-Fernández

M

, Chinea-Santiago

G

, Martín-Dunn

A M

, et al.

The SARS-CoV-2 receptor-binding domain expressed in Pichia pastoris as a candidate vaccine antigen

medRxiv, 2021. DOI: 10.1101∕2021.06.29.21259605.

[本文引用: 4]

[59]

Walls

A C

, Fiala

B

, Schäfer

A

, et al.

Elicitation of potent neutralizing antibody responses by designed protein nanoparticle vaccines for SARS-CoV-2

Cell, 2020, 183(5): 1367-1382.e17.

[60]

Pérez-Rodríguez

S

, de la Caridad Rodríguez-González

M

, Ochoa-Azze

R

, et al.

A randomized, double-blind phase I clinical trial of two recombinant dimeric RBD COVID-19 vaccine candidates: safety, reactogenicity and immunogenicity

Vaccine, 2022, 40(13): 2068-2075.

PMID:35164986 [本文引用: 4]

The Receptor Binding Domain (RBD) of the SARS-CoV-2 spike protein is the target for many COVID-19 vaccines. Here we report results for phase I clinical trial of two COVID-19 vaccine candidates based on recombinant dimeric RBD (d-RBD).We performed a randomized, double-blind, phase I clinical trial in the National Centre of Toxicology in Havana. Sixty Cuban volunteers aged 19-59 years were randomized into three groups (20 subjects each): 1) FINLAY-FR-1 (50 µg d-RBD plus outer membrane vesicles from N. meningitidis); 2) FINLAY-FR-1A-50 (50 µg d-RBD, three doses); 3) FINLAY-FR-1A-25 (25 µg d-RDB, three doses). The FINLAY-FR-1 group was randomly divided to receive a third dose of the same vaccine candidate (homologous schedule) or FINLAY-FR-1A-50 (heterologous schedule). The primary outcomes were safety and reactogenicity. The secondary outcome was vaccine immunogenicity. Humoral response at baseline and following each vaccination was evaluated using live-virus neutralization test, anti-RBD IgG ELISA and in-vitro neutralization test of RBD:hACE2 interaction.Most adverse events were of mild intensity (63.5%), solicited (58.8%), and local (61.8%); 69.4% with causal association with vaccination. Serious adverse events were not found. The FINLAY-FR-1 group reported more subjects with adverse events than the other two groups. After the third dose, anti-RBD seroconversion was 100%, 94.4% and 90% for the FINLAY-FR-1, FINLAY-FR-1A-50 and FINLAY-FR-1A-25 respectively. The in-vitro inhibition of RBD:hACE2 interaction increased after the second dose in all formulations. The geometric mean neutralizing titres after the third dose rose significantly in the group vaccinated with FINLAY-FR-1 with respect to the other formulations and the COVID-19 Convalescent Serum Panel. No differences were found between FINLAY-FR-1 homologous or heterologous schedules.Vaccine candidates were safe and immunogenic, and induced live-virus neutralizing antibodies against SARS-CoV-2. The highest values were obtained when outer membrane vesicles were used as adjuvant.https://rpcec.sld.cu/en/trials/RPCEC00000338-En.Copyright © 2022 Elsevier Ltd. All rights reserved.

[61]

Bravo

L

, Smolenov

I

, Han

H H

, et al.

Efficacy of the adjuvanted subunit protein COVID-19 vaccine, SCB-2019: a phase 2 and 3 multicentre, double-blind, randomised, placebo-controlled trial

The Lancet, 2022, 399(10323): 461-472.

[62]

Lien

C E

, Kuo

T Y

, Lin

Y J

, et al.

Evaluating the neutralizing ability of a CpG-adjuvanted S-2P subunit vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern

Clinical Infectious Diseases: an Official Publication of the Infectious Diseases Society of America, 2021, 2021Nov5: ciab711.

[63]

Nanishi

E

, Borriello

F

, O’Meara

T R

, et al.

An aluminum hydroxide: CpG adjuvant enhances protection elicited by a SARS-CoV-2 receptor binding domain vaccine in aged mice

Science Translational Medicine, 2022, 14(629): eabj5305.

[64]

Liu

H T

, Zhou

C L

, An

J

, et al.

Development of recombinant COVID-19 vaccine based on CHO-produced, prefusion spike trimer and alum∕CpG adjuvants

Vaccine, 2021, 39(48): 7001-7011.

[65]

Tian

J H

, Patel

N

, Haupt

R

, et al.

SARS-CoV-2 spike glycoprotein vaccine candidate NVX-CoV 2373 immunogenicity in baboons and protection in mice

Nature Communications, 2021, 12: 372.

[66]

Sridhar

S

, Joaquin

A

, Bonaparte

M I

, et al.

Safety and immunogenicity of an AS03-adjuvanted SARS-CoV-2 recombinant protein vaccine (CoV 2 preS dTM) in healthy adults: interim findings from a phase 2, randomised, dose-finding, multicentre study

The Lancet Infectious Diseases, 2022, S1473- (21)00764-7.

[67]

Watterson

D

, Wijesundara

D K

, Modhiran

N

, et al.

Preclinical development of a molecular clamp-stabilised subunit vaccine for severe acute respiratory syndrome coronavirus 2

Clinical & Translational Immunology, 2021, 10(4): e1269.

[68]

Li

L

, Honda-Okubo

Y

, Huang

Y

, et al.

Immunisation of ferrets and mice with recombinant SARS-CoV-2 spike protein formulated with Advax-SM adjuvant protects against COVID-19 infection

Vaccine, 2021, 39(40): 5940-5953.

[69]

Hsieh

S M

, Liu

M C

, Chen

Y H

, et al.

Safety and immunogenicity of CpG 1018 and aluminium hydroxide-adjuvanted SARS-CoV-2 S-2P protein vaccine MVC-COV1901: interim results of a large-scale, double-blind, randomised, placebo-controlled phase 2 trial in Taiwan

The Lancet Respiratory Medicine, 2021, 9(12): 1396-1406.

[70]

Keech

C

, Albert

G

, Cho

I

, et al.

Phase 1-2 trial of a SARS-CoV-2 recombinant spike protein nanoparticle vaccine

The New England Journal of Medicine, 2020, 383(24): 2320-2332.

[71]

Novavax. The registered clinical trials of Nuvaxovid. [2022-04-18]. https://covid19.trackvaccines.org/vaccines/25/.

[72]

Serum Institute of India. The registered clinical trials of COVOVAX (Novavax formulation). [2022-04-18]. https://covid19.trackvaccines.org/vaccines/123/.

[73]

Thuluva

S

, Paradkar

V

, Turaga

K

, et al.

Selection of optimum formulation of RBD-based protein sub-unit COVID-19 vaccine (Corbevax) based on safety and immunogenicity in an open-label, randomized phase-1 and 2 clinical studies

medRxiv, 2022. DOI: 10.1101/2022.03.08.22271822.

[74]

Zhao

X

, Zheng

A Q

, Li

D D

, et al.

Neutralization of recombinant RBD-subunit vaccine ZF2001-elicited antisera to SARS-CoV-2 variants including Delta

bioRxiv, 2021. DOI: 10.1101/2021.07.15.452504.

[75]

Kaabi

N A

, Yang

Y K

, Du

L F

, et al.

Safety and immunogenicity of a hybrid-type vaccine booster in BBIBP-CorV recipients: a randomized controlled phase 2 trial

medRxiv, 2022. DOI: 10.1101/2022.03.08.22272062.

[76]

Valdes-Balbin

Y

, Santana-Mederos

D

, Quintero

L

, et al.

SARS-CoV-2 RBD-tetanus toxoid conjugate vaccine induces a strong neutralizing immunity in preclinical studies

ACS Chemical Biology, 2021, 16(7): 1223-1233.

PMID:34219448 [本文引用: 3]

Controlling the global COVID-19 pandemic depends, among other measures, on developing preventive vaccines at an unprecedented pace. Vaccines approved for use and those in development intend to elicit neutralizing antibodies to block viral sites binding to the host's cellular receptors. Virus infection is mediated by the spike glycoprotein trimer on the virion surface via its receptor binding domain (RBD). Antibody response to this domain is an important outcome of immunization and correlates well with viral neutralization. Here, we show that macromolecular constructs with recombinant RBD conjugated to tetanus toxoid (TT) induce a potent immune response in laboratory animals. Some advantages of immunization with RBD-TT conjugates include a predominant IgG immune response due to affinity maturation and long-term specific B-memory cells. These result demonstrate the potential of the conjugate COVID-19 vaccine candidates and enable their advance to clinical evaluation under the name SOBERANA02, paving the way for other antiviral conjugate vaccines.

[77]

Liu

H

, Su

D

, Zhang

J

, et al.

Improvement of pharmacokinetic profile of TRAIL via trimer-tag enhances its antitumor activity in vivo

Scientific Reports, 2017, 7: 8953.

[78]

Liang

J G

, Su

D

, Song

T Z

, et al.

S-Trimer, a COVID-19 subunit vaccine candidate, induces protective immunity in nonhuman primates

Nature Communications, 2021, 12: 1346.

[79]

Chappell

K J

, Mordant

F L

, Li

Z Y

, et al.

Safety and immunogenicity of an MF59-adjuvanted spike glycoprotein-clamp vaccine for SARS-CoV-2: a randomised, double-blind, placebo-controlled, phase 1 trial

The Lancet Infectious Diseases, 2021, 21(10): 1383-1394.

[80]

Liu

Y

, Zhang

N

, Wang

B

, et al.

Broad and long-lasting immune response against SARS-CoV-2 Omicron and other variants by PIKA-adjuvanted recombinant SARS-CoV-2 spike (S) protein subunit vaccine (YS-SC2-010)

bioRxiv, 2021. DOI: 10.1101/2021.12.22.473615.

[81]

Tong

J

, Zhu

C X

, Lai

H Y

, et al.

Potent neutralization antibodies induced by a recombinant trimeric spike protein vaccine candidate containing PIKA adjuvant for COVID-19

Vaccines, 2021, 9(3): 296.

[82]

Heath

P T

, Galiza

E P

, Baxter

D N

, et al.

Safety and efficacy of NVX-CoV 2373 COVID-19 vaccine

The New England Journal of Medicine, 2021, 385(13): 1172-1183.

PMID:34192426 [本文引用: 1]

Early clinical data from studies of the NVX-CoV2373 vaccine (Novavax), a recombinant nanoparticle vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that contains the full-length spike glycoprotein of the prototype strain plus Matrix-M adjuvant, showed that the vaccine was safe and associated with a robust immune response in healthy adult participants. Additional data were needed regarding the efficacy, immunogenicity, and safety of this vaccine in a larger population.In this phase 3, randomized, observer-blinded, placebo-controlled trial conducted at 33 sites in the United Kingdom, we assigned adults between the ages of 18 and 84 years in a 1:1 ratio to receive two intramuscular 5-μg doses of NVX-CoV2373 or placebo administered 21 days apart. The primary efficacy end point was virologically confirmed mild, moderate, or severe SARS-CoV-2 infection with an onset at least 7 days after the second injection in participants who were serologically negative at baseline.A total of 15,187 participants underwent randomization, and 14,039 were included in the per-protocol efficacy population. Of the participants, 27.9% were 65 years of age or older, and 44.6% had coexisting illnesses. Infections were reported in 10 participants in the vaccine group and in 96 in the placebo group, with a symptom onset of at least 7 days after the second injection, for a vaccine efficacy of 89.7% (95% confidence interval [CI], 80.2 to 94.6). No hospitalizations or deaths were reported among the 10 cases in the vaccine group. Five cases of severe infection were reported, all of which were in the placebo group. A post hoc analysis showed an efficacy of 86.3% (95% CI, 71.3 to 93.5) against the B.1.1.7 (or alpha) variant and 96.4% (95% CI, 73.8 to 99.5) against non-B.1.1.7 variants. Reactogenicity was generally mild and transient. The incidence of serious adverse events was low and similar in the two groups.A two-dose regimen of the NVX-CoV2373 vaccine administered to adult participants conferred 89.7% protection against SARS-CoV-2 infection and showed high efficacy against the B.1.1.7 variant. (Funded by Novavax; EudraCT number, 2020-004123-16.).Copyright © 2021 Massachusetts Medical Society.

[83]

Shinde

V

, Bhikha

S

, Hoosain

Z

, et al.

Efficacy of NVX-CoV 2373 COVID-19 vaccine against the B.1.351 variant

The New England Journal of Medicine, 2021, 384(20): 1899-1909.

PMID:33951374 [本文引用: 1]

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the coronavirus disease 2019 (Covid-19) pandemic. In a phase 1-2 trial involving healthy adults, the NVX-CoV2373 nanoparticle vaccine had an acceptable safety profile and was associated with strong neutralizing-antibody and antigen-specific polyfunctional CD4+ T-cell responses. Evaluation of vaccine efficacy was needed in a setting of ongoing SARS-CoV-2 transmission.In this phase 2a-b trial in South Africa, we randomly assigned human immunodeficiency virus (HIV)-negative adults between the ages of 18 and 84 years or medically stable HIV-positive participants between the ages of 18 and 64 years in a 1:1 ratio to receive two doses of either the NVX-CoV2373 vaccine (5 μg of recombinant spike protein with 50 μg of Matrix-M1 adjuvant) or placebo. The primary end points were safety and vaccine efficacy against laboratory-confirmed symptomatic Covid-19 at 7 days or more after the second dose among participants without previous SARS-CoV-2 infection.Of 6324 participants who underwent screening, 4387 received at least one injection of vaccine or placebo. Approximately 30% of the participants were seropositive for SARS-CoV-2 at baseline. Among 2684 baseline seronegative participants (94% HIV-negative and 6% HIV-positive), predominantly mild-to-moderate Covid-19 developed in 15 participants in the vaccine group and in 29 in the placebo group (vaccine efficacy, 49.4%; 95% confidence interval [CI], 6.1 to 72.8). Vaccine efficacy among HIV-negative participants was 60.1% (95% CI, 19.9 to 80.1). Of 41 sequenced isolates, 38 (92.7%) were the B.1.351 variant. Post hoc vaccine efficacy against B.1.351 was 51.0% (95% CI, -0.6 to 76.2) among the HIV-negative participants. Preliminary local and systemic reactogenicity events were more common in the vaccine group; serious adverse events were rare in both groups.The NVX-CoV2373 vaccine was efficacious in preventing Covid-19, with higher vaccine efficacy observed among HIV-negative participants. Most infections were caused by the B.1.351 variant. (Funded by Novavax and the Bill and Melinda Gates Foundation; ClinicalTrials.gov number, NCT04533399.).Copyright © 2021 Massachusetts Medical Society.

[84]

Dunkle

L M

, Kotloff

K L

, Gay

C L

, et al.

Efficacy and safety of NVX-CoV 2373 in adults in the United States and Mexico

The New England Journal of Medicine, 2022, 386(6): 531-543.

[85]

Powell

A E

, Zhang

K M

, Sanyal

M

, et al.

A single immunization with spike-functionalized ferritin vaccines elicits neutralizing antibody responses against SARS-CoV-2 in mice

ACS Central Science, 2021, 7(1): 183-199.

[86]

Kanekiyo

M

, Wei

C J

, Yassine

H M

, et al.

Self-assembling influenza nanoparticle vaccines elicit broadly neutralizing H1N1 antibodies

Nature, 2013, 499 (7456): 102-106.

[87]

Yassine

H M

, Boyington

J C

, McTamney

P M

, et al.

Hemagglutinin-stem nanoparticles generate heterosubtypic influenza protection

Nature Medicine, 2015, 21 (9): 1065-1070.

PMID:26301691 [本文引用: 1]

The antibody response to influenza is primarily focused on the head region of the hemagglutinin (HA) glycoprotein, which in turn undergoes antigenic drift, thus necessitating annual updates of influenza vaccines. In contrast, the immunogenically subdominant stem region of HA is highly conserved and recognized by antibodies capable of binding multiple HA subtypes. Here we report the structure-based development of an H1 HA stem-only immunogen that confers heterosubtypic protection in mice and ferrets. Six iterative cycles of structure-based design (Gen1-Gen6) yielded successive H1 HA stabilized-stem (HA-SS) immunogens that lack the immunodominant head domain. Antigenic characterization, determination of two HA-SS crystal structures in complex with stem-specific monoclonal antibodies and cryo-electron microscopy analysis of HA-SS on ferritin nanoparticles (H1-SS-np) confirmed the preservation of key structural elements. Vaccination of mice and ferrets with H1-SS-np elicited broadly cross-reactive antibodies that completely protected mice and partially protected ferrets against lethal heterosubtypic H5N1 influenza virus challenge despite the absence of detectable H5N1 neutralizing activity in vitro. Passive transfer of immunoglobulin from H1-SS-np-immunized mice to naive mice conferred protection against H5N1 challenge, indicating that vaccine-elicited HA stem-specific antibodies can protect against diverse group 1 influenza strains.

[88]

李志鹏, 刘庆友, 石德顺.

铁蛋白纳米颗粒应用于生物医疗领域的研究进展

生物技术通报, 2015, 31(10): 38-47.

在漫长的进化过程中, 生物系统中出现了多种多样的纳米粒子。其中铁蛋白纳米粒子广泛存在于所有生物体内, 是参与生命活动的重要功能蛋白。近年来, 铁蛋白自组装纳米粒子特殊的理化性质使其在生物医学领域应用中呈现出巨大的优势和应用前景。铁蛋白纳米笼的应用主要包括微量血清铁蛋白的临床检查、作为营养物质补充机体铁需求、纳米生物材料平台和纳米材料的生物呈递等。综述了铁蛋白纳米粒子在疾病诊断与治疗以及药物呈递与疫苗开发上的应用, 并对铁蛋白纳米粒子在生物医学领域的应用前景进行展望。

Li

Z P

, Liu

Q Y

, Shi

D S

.

Research progress on application of ferritin nanoparticles in the field of biomedicine

Biotechnology Bulletin, 2015, 31(10): 38-47.

在漫长的进化过程中, 生物系统中出现了多种多样的纳米粒子。其中铁蛋白纳米粒子广泛存在于所有生物体内, 是参与生命活动的重要功能蛋白。近年来, 铁蛋白自组装纳米粒子特殊的理化性质使其在生物医学领域应用中呈现出巨大的优势和应用前景。铁蛋白纳米笼的应用主要包括微量血清铁蛋白的临床检查、作为营养物质补充机体铁需求、纳米生物材料平台和纳米材料的生物呈递等。综述了铁蛋白纳米粒子在疾病诊断与治疗以及药物呈递与疫苗开发上的应用, 并对铁蛋白纳米粒子在生物医学领域的应用前景进行展望。

[89]

Joyce

M G

, Chen

W H

, Sankhala

R S

, et al.

SARS-CoV-2 ferritin nanoparticle vaccines elicit broad SARS coronavirus immunogenicity

Cell Reports, 2021, 37(12): 110143.

[90]

Joyce

M G

, King

H A D

, Naouar

I E

, et al.

Efficacy of a broadly neutralizing SARS-CoV-2 ferritin nanoparticle vaccine in nonhuman Primates

bioRxiv, 2021. DOI: 10.1101/2021.03.24.436523.

[91]

Carmen

J M

, Shrivastava

S

, Lu

Z

, et al.

SARS-CoV-2 ferritin nanoparticle vaccine induces robust innate immune activity driving polyfunctional spike-specific T cell responses

NPJ Vaccines, 2021, 6(1): 151.

[92]

Vaxine

. COVAX-19^® vaccine project of Vaxine. [2022-04-18].https://vaxine.net/projects/.

[93]

University of Saskatchewan. A clinical trial of COVAC-2 in adults. [2022-04-18]. https://clinicaltrials.gov/ct2/show/NCT05209009.

[94]

Hospital

do Coracao

. Evaluation of safety and immunogenicity of a novel vaccine for prevention of COVID-19 in adults previously immunized. [2022-04-18]. https://clinicaltrials.gov/ct2/show/NCT05016934.

[95]

Renn

A

, Fu

Y

, Hu

X

, et al.

Fruitful neutralizing antibody pipeline brings hope to defeat SARS-CoV-2

Trends in Pharmacological Sciences, 2020, 41(11): 815-829.

[96]

Pollet

J

, Chen

W H

, Versteeg

L

, et al.

SARS-CoV-2 RBD219-N1C1: a yeast-expressed SARS-CoV-2 recombinant receptor-binding domain candidate vaccine stimulates virus neutralizing antibodies and T-cell immunity in mice

Human Vaccines & Immunotherapeutics, 2021, 17(8): 2356-2366.

[97]

Center for Genetic Engineering and Biotechnology. Phase III clinical study of Abdala. [2022-04-18]. https://www.cigb.edu.cu/en/product/abdala-cigb-66-2/.

[98]

Meng

F Y

, Gao

F

, Jia

S Y

, et al.

Safety and immunogenicity of a recombinant COVID-19 vaccine (Sf9 cells) in healthy population aged 18 years or older: two single-center, randomised, double-blind, placebo-controlled, phase 1 and phase 2 trials

Signal Transduction and Targeted Therapy, 2021, 6: 271.

[99]

Yang

J

, Wang

W

, Chen

Z

, et al.

A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity

Nature, 2020, 586 (7830): 572-577.

[100]

Huang

B Y

, Dai

L P

, Wang

H

, et al.

eutralization of SARS-CoV-2 VOC 501Y.V2 by human antisera elicited by both inactivated BBIBP-CorV and recombinant dimeric RBD ZF2001 vaccines

bioRxiv, 2021. DOI: 10.1101/2021.02.01.429069.

[101]

Guirakhoo

F

, Kuo

L

, Peng

J

, et al.

A novel SARS-CoV-2 multitope protein/peptide vaccine candidate is highly immunogenic and prevents lung infection in an adeno associated virus human angiotensin-converting enzyme 2 (AAV hACE2) mouse model

bioRxiv, 2020. DOI: 10.1101/2020.11.30.399154.

[102]

University Medical Center Groningen. Combinatorial phase I/II safety, tolerability and immunogenicity single center open-label clinical study of AKS-452 COVID-19 vaccination study. [2022-04-18]. https://clinicaltrials.gov/ct2/show/NCT04681092.

[103]

Baiya Phytopharm. A study to evaluate safety, tolerability, and reactogenicity of an RBD-Fc-based vaccine to prevent COVID-19. [2022-04-18]. https://clinicaltrials.gov/ct2/show/NCT04953078.

[104]

Yu

J P

, Yao

W R

, Hu

Y S

, et al.

A trimeric NTD and RBD SARS-CoV-2 subunit vaccine induced protective immunity in CAG-hACE 2 transgenic mice and rhesus macaques

bioRxiv, 2021. DOI: 10.1101/2021.11.03.467182.

[105]

Maharjan

P M

, Choe

S

.

Plant-based COVID-19 vaccines: current status, design, and development strategies of candidate vaccines

Vaccines, 2021, 9(9): 992.

[106]

Huang

W C

, Zhou

S Q

, He

X D

, et al.

SARS-CoV-2 RBD neutralizing antibody induction is enhanced by particulate vaccination

Advanced Materials, 2020, 32(50): 2005637.

[107]

Zheng

N Y

, Xia

R

, Yang

C P

, et al.

Boosted expression of the SARS-CoV nucleocapsid protein in tobacco and its immunogenicity in mice

Vaccine, 2009, 27(36): 5001-5007.

[108]

Interfax. EpiVacCorona vaccine to be efficacious against Omicron variant. [2022-04-18]. https://interfax.com/newsroom/top-stories/73354/.

[109]

Heitmann

J S

, Bilich

T

, Tandler

C

, et al.

A COVID-19 peptide vaccine for the induction of SARS-CoV-2 T cell immunity

Nature, 2022, 601 (7894): 617-622.

[110]

Cao

Y

, Hao

X

, Wang

X

, et al.

Humoral immunogenicity and reactogenicity of CoronaVac or ZF2001 booster after two doses of inactivated vaccine

Cell Research, 2022, 32 (1): 107-109.

[111]

Ai

J

, Zhang

H

, Zhang

Q

, et al.

Recombinant protein subunit vaccine booster following two-dose inactivated vaccines dramatically enhanced anti-RBD responses and neutralizing titers against SARS-CoV-2 and variants of concern

Cell Research, 2022, 32 (1): 103-106.

[112]

Novavax. Evaluation of the safety and immunogenicity of SII Vaccine constructs based on the SARS-CoV-2 (COVID-19) variant in adults. [2022-04-18]. https://clinicaltrials.gov/ct2/show/NCT05029856.

URL [本文引用: 5]

[113]

Sanofi. Sanofi and GSK announce positive preliminary booster data for their COVID-19 vaccine candidate and continuation of phase 3 trial per independent monitoring board recommendation. [2022-04-18]. https://www.sanofi.com/en/media-room/press-releases/2021/2021-12-15-07-30-00-2352255.

[114]

Clover Biopharmaceuticals. Immunogenicity and safety of adjuvanted SCB-2020S vaccines in adults. [2022-04-18]. https://www.clinicaltrials.gov/ct2/show/NCT04950751.

[115]

Barreiro

A

, Prenafeta

A

, Bech-Sabat

G

, et al.

Preclinical efficacy, safety, and immunogenicity of PHH-1V, a second-generation COVID-19 vaccine candidate based on a novel recombinant RBD fusion heterodimer of SARS-CoV-2

bioRxiv, 2021. DOI: 10.1101/2021.11.22.469117.

[116]

Saville

J W

, Mannar

D

, Zhu

X

, et al.

Structural and biochemical rationale for enhanced spike protein fitness in delta and kappa SARS-CoV-2 variants

Nature Communications, 2022, 13(1): 742.

PMID:35136050 [本文引用: 1]

The Delta and Kappa variants of SARS-CoV-2 co-emerged in India in late 2020, with the Delta variant underlying the resurgence of COVID-19, even in countries with high vaccination rates. In this study, we assess structural and biochemical aspects of viral fitness for these two variants using cryo-electron microscopy (cryo-EM), ACE2-binding and antibody neutralization analyses. Both variants demonstrate escape of antibodies targeting the N-terminal domain, an important immune hotspot for neutralizing epitopes. Compared to wild-type and Kappa lineages, Delta variant spike proteins show modest increase in ACE2 affinity, likely due to enhanced electrostatic complementarity at the RBD-ACE2 interface, which we characterize by cryo-EM. Unexpectedly, Kappa variant spike trimers form a structural head-to-head dimer-of-trimers assembly, which we demonstrate is a result of the E484Q mutation and with unknown biological implications. The combination of increased antibody escape and enhanced ACE2 binding provides an explanation, in part, for the rapid global dominance of the Delta variant.© 2022. The Author(s).

[117]

National Taiwan University Hospital. A heterologous prime-boost study to evaluate immunogenicity and safety of mRNA-1273 with MVC-COV1901 in adults. [2022-04-18]. https://clinicaltrials.gov/ct2/show/NCT05079633.

[118]

Yisheng

Biopharma

. To evaluate the safety, tolerability, and immunogenicity of a PIKA-adjuvanted recombinant SARS-CoV-2 spike (S) protein subunit vaccine in healthy individuals. [2022-04-18]. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382358&isReview=true.

[119]

CinnaGen

Company

. A phase III, randomized, two-armed, double-blind, placebo controlled trial to evaluate efficacy and safety of an adjuvanted recombinant SARS-CoV-2 spike (S) protein subunit vaccine (Spikogen^® produced by CinnaGen Co. [2022-04-18]. https://en.irct.ir/trial/57559.

[120]

Novavax. A study to evaluate the efficacy, immune response, and safety of a COVID-19 vaccine in adults ≥ 18 years with a pediatric expansion in adolescents (12 to ≥ 18 years) at risk for SARS-CoV-2. [2022-04-18]. https://clinicaltrials.gov/ct2/show/NCT04611802.

[121]

Center for Genetic Engineering and Biotechnology. Phase III, multicenter, randomized, double-blind, placebo-controlled clinical trial for the evaluation in adults of the efficacy, safety and immunogenicity of the vaccine candidate CIGB-66 against SARS-CoV-2. [2022-04-18]. https://rpcec.sld.cu/trials/RPCEC00000359-En.

[122]

Biological

E Limited

. A prospective, single-blind, randomized, active-controlled phase III clinical study to evaluate the immunogenicity and safety of Biological E’s Corbevax vaccine for protection against COVID-19 disease when administered to RT-PCR negative adult subjects. [2022-04-18]. http://www.ctri.nic.in/Clinicaltrials/pmaindet2.php?trialid=59772.

[123]

National Vaccine and Serum Institute, China. Clinical trial on sequential immunization of recombinant COVID-19 vaccine (CHO cells, NVSI-06-08) and inactivated COVID-19 vaccine (Vero cells) in population aged 18 years and above. [2022-04-18]. https://clinicaltrials.gov/ct2/show/NCT05069129.

[124]

Finlay Vaccine Institute. Phase III clinical trial, multicenter, adaptive, parallel-group, randomized, placebo-controlled, double-blind study to evaluate the efficacy, safety and immunogenicity of vaccination against SARS-CoV-2 with 2 doses of FINLAY-FR-2 and a heterologous scheme with 2 doses of FINLAY-FR-2 and a booster dose with FINLAY-FR-1A (COVID-19). [2022-04-18]. http://rpcec.sld.cu/en/trials/RPCEC00000354-En.

[125]

Kentucky

BioProcessing

. KBP-201 COVID-19 vaccine trial in healthy volunteers. [2022-04-18]. https://clinicaltrials.gov/ct2/show/NCT04473690.