The first COVID-19 vaccine to reach phase 1 clinical trial has been found to be safe, well-tolerated, and able to generate an immune response against SARS-CoV-2 in humans, according to new research published in The Lancet.
The open-label trial in 108 healthy adults demonstrates promising results after 28 days – the final results will be evaluated in six months. Further trials are needed to tell whether the immune response it elicits effectively protects against SARS-CoV-2 infection.
“These results represent an important milestone. The trial demonstrates that a single dose of the new adenovirus type 5 vectored COVID-19 (Ad5-nCoV) vaccine produces virus-specific antibodies and T cells in 14 days, making it a potential candidate for further investigation,” says Professor Wei Chen from the Beijing Institute of Biotechnology in Beijing, China, who is responsible for the study.
“However, these results should be interpreted cautiously. The challenges in the development of a COVD-19 vaccine are unprecedented, and the ability to trigger these immune responses does not necessarily indicate that the vaccine will protect humans from COVID-19.
This result shows a promising vision for the development of COVID-19 vaccines, but we are still a long way from this vaccine being available to all.”
The creation of an effective vaccine is seen as the long-term solution to controlling the COVID-19 pandemic. Currently, there are more than 100 candidate COVID-19 vaccines in development worldwide.
The new Ad5 vectored COVID-19 vaccine evaluated in this trial is the first to be tested in humans. It uses a weakened common cold virus (adenovirus, which infects human cells readily but is incapable of causing disease) to deliver genetic material that codes for the SARS-CoV-2 spike protein to the cells.
These cells then produce the spike protein, and travel to the lymph nodes where the immune system creates antibodies that will recognize that spike protein and fight off the coronavirus.
The trial assessed the safety and ability to generate an immune response of different dosages of the new Ad5-nCoV vaccine in 108 healthy adults between the ages of 18 and 60 years who did not have SARS-CoV-2 infection.
Volunteers were enrolled from one site in Wuhan, China, and assigned to receive either a single intramuscular injection of the new Ad5 vaccine at a low dose (5 × 1010 viral particles/0·5ml, 36 adults), middle dose (1×1011 viral particles/1.0ml, 36 adults), or high dose (1.5 x 1011 viral particles/1.5ml, 36 adults).
The researchers tested the volunteers’ blood at regular intervals following vaccination to see whether the vaccine stimulated both arms of the immune system: the body’s ‘humoral response’ (the part of the immune system that produces neutralising antibodies which can fight infection and could offer a level of immunity), and the body’s cell-mediated arm (which depends on a group of T cells, rather than antibodies, to fight the virus). The ideal vaccine might generate both antibody and T cell responses to defend against SARS-CoV-2.
The vaccine candidate was well tolerated at all doses with no serious adverse events reported within 28 days of vaccination. Most adverse events were mild or moderate, with 83% (30/36) of those receiving low and middle doses of the vaccine and 75% (27/36) in the high dose group reporting at least one adverse reaction within 7 days of vaccination.
The most common adverse reactions were mild pain at the injection site reported in over half (54%, 58/108) of vaccine recipients, fever (46%, 50/108), fatigue (44%, 47/108), headache (39%, 42/108), and muscle pain (17%, 18/108).
One participant given the higher dose vaccine reported severe fever along with severe symptoms of fatigue, shortness of breath, and muscle pain—however these adverse reactions persisted for less than 48 hours.
Within two weeks of vaccination, all dose levels of the vaccine triggered some level of immune response in the form of binding antibodies (that can bind to the coronavirus but do not necessarily attack it – low-dose group 16/36, 44%; medium dose 18/36, 50%; high dose 22/36, 61%), and some participants had detectable neutralising antibodies against SARS-CoV-2 (low-dose group 10/36, 28%; medium dose 11/36, 31%; high dose 15/36, 42%).
After 28 days, most participants had a four-fold increase in binding antibodies (35/36, 97% low-dose group; 34/36 (94%) middle-dose group, and 36/36, 100% in high-dose group), and half (18/36) of participants in the low- and middle-dose groups and three-quarters (27/36) of those in the high-dose group showed neutralising antibodies against SARS-CoV-2.
Importantly, the Ad5-nCoV vaccine also stimulated a rapid T cell response in the majority of volunteers, which was greater in those given the higher and middle doses of vaccine, with levels peaking at 14 days after vaccination (low-dose group (30/36; 83.3%), medium (35/36, 97.2%), and high-dose group (35/36, 97.2%) at 14 days).
Further analyses showed that 28 days after vaccination, the majority of recipients showed either a positive T cell response or had detectable neutralising antibodies against SARS-CoV-2 (low-dose group 28/36, 78%; medium-dose group 33/36, 92%; high-dose group 36/36, 100%).
However, the authors note that both the antibody and T-cell response could be reduced by high pre-existing immunity to adenovirus type 5 (the common cold virus vector/carrier)—in the study, 44%-56% of participants in the trial had high pre-existing immunity to adenovirus type 5, and had a less positive antibody and T-cell response to the vaccine.
“Our study found that pre-existing Ad5 immunity could slow down the rapid immune responses to SARS-CoV-2 and also lower the peaking level of the responses. Moreover, high pre-existing Ad5 immunity may also have a negative impact on the persistence of the vaccine-elicited immune responses,” say Professor Feng-Cai Zhu from Jiangsu Provincial Center for Disease Control and Prevention in China who led the study.
The authors note that the main limitations of the trial are its small sample size, relatively short duration, and lack of randomised control group, which limits the ability to pick up rarer adverse reactions to the vaccine or provide robust evidence for its ability to generate an immune reaction. Further research will be needed before this trial vaccine becomes available to all.
A randomised, double-blinded, placebo-controlled phase 2 trial of the Ad5-nCoV vaccine has been initiated in Wuhan to determine whether the results can be replicated, and if there are any adverse events up to 6 months after vaccination, in 500 healthy adults – 250 volunteers given a middle dose, 125 given a low dose, and 125 given a placebo as a control. For the first time, this will include participants over 60 years old, an important target population for the vaccine.
Coronavirus disease 2019 (COVID-2019), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China in December 2019 and has spread rapidly across the world due to its high transmissibility and pathogenicity (Munster et al., 2020, Zhu et al., 2020). SARS-CoV-2 is a distinct clade of beta coronaviruses encompassing severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) (Lu et al., 2020).
Although most cases of the disease caused by most pathogenic coronaviruses are mild (Su et al., 2016), the SARS-CoV and MERS-CoV outbreaks in 2002 and 2012, respectively, demonstrated their high lethality (Schoeman and Fielding, 2019). SARS-CoV-2 bears an 82% resemblance to the genomic sequence of SARS-CoV (Chan et al., 2020); however, COVID-19 presents a lower case fatality rate and higher infectiousness than SARS, with mortality rates of approximately 3.7% for COVID-19 and 10% for SARS (WHO, 2003, WHO, 2020a).
COVID-19 patients often exhibit mild symptoms, such as fever, cough, myalgia, and fatigue and generally have a good prognosis. However, a large proportion of COVID-19 cases have rapidly progressed to severe types, especially among older men with underlying diseases (Chen et al., 2020c, Huang et al., 2020, Liu et al., 2020c, Wang et al., 2020a).
Severe cases can include dyspnea (Lin et al., 2020), shock (Wang et al., 2020a), organ dysfunction [acute respiratory distress syndrome (ARDS)] (Guan et al., 2020, Wang et al., 2020a, Xu et al., 2020, Yang et al., 2020, Yao et al., 2020), acute cardiac injury (Han et al., 2020a, Strabelli and Uip, 2020, Wang et al., 2020a, Yao et al., 2020, Zhou et al., 2020a), acute kidney injury (Guan et al., 2020, Li et al., 2020a, Pan et al., 2020, Wang et al., 2020a, Yao et al., 2020), acute liver injury (Xie et al., 2020, Xu et al., 2020, Yao et al., 2020; Zhang et al., 2020a), neurological injury (Mao et al., 2020, Wu et al., 2020), gastrointestinal injury (Yao et al., 2020), immune injury (Chen et al., 2020b, Guan et al., 2020, Qin et al., 2020, Wang et al., 2020b, Xu et al., 2020, Yao et al., 2020, Liu et al., 2020b, Zheng et al., 2020), coagulation impairment (Han et al., 2020b, Tang et al., 2020a), and even death (Huang et al., 2020, Wang et al., 2020a) (Fig. 1 ).
In addition, COVID-19 pandemic has great impact on psychological stress and mental health worldwide (Bao et al., 2020, Kang et al., 2020, Li et al., 2020, Pfefferbaum and North, 2020, Shi et al., 2020a).
SARS-CoV-2 infection-induced impairment of multiple organ function Impairment of multiple organ function by SARS-CoV-2 infection includes acute respiratory distress syndrome (ARDS), acute cardiac injury, acute kidney injury, acute liver injury, neurological injury, gastrointestinal injury, immune system injury, and coagulation impairment. Abbreviations: ALT, alanine transaminase; APTT, activated partial thromboplastin time; ARDS, acute respiratory distress syndrome; AST, aspartate aminotransferase; CK-MB, creatine kinase myocardial band; CNS, central nervous system; FDP, fibrinogen degradation products; HLA-DR, human leukocyte antigen DR; INR, international normalized ratio; LDH, lactate dehydrogenase; MYO, myoglobin; NK, natural killer cell; NT-proBNP, N terminal pro-B-type natriuretic peptide; PaO2/FiO2, oxygenation index; PNS, peripheral nervous system; PT, prothrombin time; RAAS, renin-angiotensin-aldosterone system; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; TBIL, total bilirubin; Th, helper T cell; TNI, troponin I.
At present, the pathogenesis and etiology of COVID-19 remain unclear, and there are no targeted therapies for COVID-19 patients, who are empirically administered symptomatic treatments, with organ support for those who are seriously ill (Wang et al., 2020a).
Given the pandemic spread of COVID-19 and the resulting global economic loss, developing alternative agents to contain SARS-CoV-2 is imperative. In this review, we summarize the potential therapeutic candidates under development for COVID-19 based on clinical trials and describe their potential mechanisms of action (Fig. 2 and Fig. 3 ).
The hypothetical replication cycle of SARS-CoV-2 and the possible targets of anti-COVID-19 drugs. SARS-CoV-2 binds to the ACE2 receptor on the surface of cells using the Spike protein, which subsequently triggers endocytosis. On releasing the viral nucleocapsid to the cytoplasm, encapsidated positive-strand genomic RNA [(+)gRNA] serves as a template to translate polypeptide chains, which are cleaved to non-structural proteins including RNA-dependent RNA polymerase. The single negative strand RNA [(-)gRNA] synthesized from (+)gRNA template is employed to replicate more copies of viral RNAs. Subgenomic RNAs (sgRNAs) are synthesized by discontinuous transcription from the (+)gRNA template and then encode viral structural and accessary proteins, which are subsequently assembled with newly synthesized viral RNA to form new virions. The nascent virions are then transported in secretory vesicles to the plasma membrane and released by exocytosis. RhACE2, convalescent plasma and JAK inhibitor baricitinib could dampen the binding of the Spike protein on the surface of the SARS-CoV-2 to ACE2 expressed on the cell surface. Lopinavir/ritonavir and favipiravir inhibit the proteolysis of polypeptide chains. Remdesivir inhibits RNA-dependent RNA polymerase. EIDD-2801 could inhibit SARS-CoV-2 replication. NO and Zinc might inhibit SARS-CoV-2 replication. Vitamin D might induce antimicrobial peptides to reduce SARS-CoV-2 replication. Ivermectin could effectively block SARS-CoV-2 growth. Baricitinib could interrupt the passage of SARS-CoV-2 entering cells through inhibition of AAK1-mediated endocytosis. CQ and HCQ inhibit virus/cell fusion process. LHQW and IFNs could block the process of virus replication (RNAs transcription, protein translation, and post-translational modification). Abbreviations: AAK1, adaptor-associated kinase 1; CQ, chloroquine; ER, endoplasmic reticulum; HCQ, hydroxychloroquine sulfate; IFNs, interferons; iNO, inhaled nitric oxide; JAK, janus kinase; LHQW, Lianhua Qingwen; rhACE2, recombinant human angiotensin-converting enzyme 2; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
The hypothetical mechanisms of SARS-CoV-2 infection-induced cytokine storm and antiviral immunity and the possible therapeutic targets of patients with COVID-19 infection. “Cytokine storms” might start with inflammatory cytokine secretion into lung tissue and pulmonary blood vessels from virus-infected alveolar epithelial cells, pulmonary vascular endothelial cells, alveolar macrophages, multinucleated giant cells, and other infiltrated immune cells, which mainly serve to limit the replication and spreading of the virus and to induce downstream immune responses via the blood circulation. Following the recruitment and activation by primary cytokines, systemic immune cells (neutrophils, DCs, Mo-M[var phi], NK cells, CD4+ T cells, CD8+ T cells, Th1 cells, Th2 cells, and Th17 cells, etc.) further secrete inflammatory cytokines and promote the cascade of inflammatory processes to eliminate virus and virus-infected cells. Vitamin C might inhibit SARS-CoV-2 and alleviate the illness by decreasing inflammatory cytokines, stimulating IFN production, supporting lymphocyte proliferation, boosting the phagocytic capability of neutrophils, monocytes, and macrophages, protecting lung barrier function and reducing lung vascular injury, increasing IFN secretion from alveolar M[var phi], Mo-M[var phi], DCs, NK cells, and CD8+ T cells. IFNs could enhance NK cell cytotoxicity, enhance expression of major histocompatibility complex Ⅰ proteins, and promote the production of IFNs and the proliferation of NK cells and M[var phi]. Bevacizumab could reduce vascular permeability. Vaccines (mRNA1273, Ad5-nCoV, PittCoVacc, and NVX-CoV2373) could induce protective antiviral immune memory, while MSCs could decrease pro-inflammatory cytokines, promote regeneration, secrete multiple paracrine factors and anti-inflammatory cytokines, and enlarge the proportion of Treg cells. iNO could alleviate pulmonary hypertension through its selective pulmonary vasodilation. Corticosteroids, LHQW, Xuebijing, IVIG, tocilizumab, sarilumab, baricitinib, vitamin D, CQ, and HCQ could also reduce inflammation. Heparin blocks the thrombus formation. Abbreviations: AT I, type I alveolar epithelial cell; AT Ⅱ, type Ⅱ alveolar epithelial cell; CQ, chloroquine; DC, dendritic cell; G-CSF, granulocyte-colony stimulating factor; HCQ, hydroxychloroquine sulfate; IFN-γ, interferon gamma; IL, interleukin; iNO, inhaled nitric oxide; IP-10, interferon-inducible protein-10; IVIG, intravenous gamma globulin; LHQW, Lianhua Qingwen; MCP-1, monocyte chemotactic protein 1; MIP-1A, macrophage inflammatory protein-1a; Mo-M[var phi], monocyte-macrophage; MSCs, mesenchymal stem cells; NK, natural killer cell; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2; Th, helper T cell; TNF-α, tumor necrosis factor alpha; Treg, regulatory T cell.
Vaccine
There is no specific vaccine currently available for containing COVID-19 infection. To meet the urgent need for an effective vaccine in the context of active SARS-CoV-2 transmission, companies and institutions worldwide have been working on a SARS-CoV-2 vaccine through various approaches, resulting in a series of vaccine candidates (Routley, 2020).
One of the most promising one of them is mRNA-1273, which is developed by National Institute of Allergy and Infectious Disease scientists together with biotechnology company Moderna (Fig. 3) (Moderna, 2020a; NIH, 2020).
As an mRNA vaccine, mRNA-1273 embedded in lipid nanoparticles encodes viral S proteins of SARS-CoV-2 and then delivers the antigen into human cells to elicit SARS-CoV-2-specific neutralizing antibodies and potent immune responses, thereby protecting healthy individuals against COVID-19 infection (Fig. 3).
mRNA vaccine is superior to other conventional vaccines, given its high potency, short production cycles and safety as lack of actual viral genome (Ahn et al., 2020). A phase Ⅰ, open-label, dose-ranging trial of mRNA-1273 was conducted in 45 healthy adult volunteers aged 18 to 55 years with three different doses of mRNA-1273 to assess its efficacy and appropriate effective dose (Table 1) (NCT04283461). On April 16, 2020, Moderna received the award from US Government Agency BRADA for up to $483 million to accelerate development of mRNA-1273 against COVID-19 (Moderna, 2020b).
mRNA-1273 was the first vaccine to be tested in a clinical trial, followed closely by another promising candidate called Ad5-nCoV, which was jointly developed by Tianjin-based biotechnology company Cansino and the Institute of Biotechnology of the Academy of Military Medical Sciences.
Developed with Cansino’s adenovirus-based viral vector vaccine technology platform, Ad5-nCoV uses replication-defective adenovirus type 5 as a vector to load SARS-CoV-2 gene fragments onto it to express the SARS-CoV-2 S protein (Fig. 3) (Shi et al., 2020b).
According to Cansino, preclinical data in animal models demonstrated that Ad5-nCoV can elicit robust immune responses and a favorable safety profile (Mak, 2020). Currently, the phase Ⅰ clinical trial evaluating the safety and efficacy of Ad5-nCoV has been initiated in Wuhan (Table 1) (Shi et al., 2020b).
A recently published study in the Lancet introduced a newly developed potentially effective SARS-CoV-2 vaccine named PittCoVacc, short for Pittsburgh Coronavirus Vaccine, developed by University of Pittsburgh School of Medicine scientists (Kim et al., 2020).
PittCoVacc uses S-protein fragments of SARS-CoV-2 to stimulate the generation of specific antibodies (Fig. 3). PittCoVacc is delivered with a novel technique known as microneedle array, a fingertip-sized patch of 400 tiny needles. This strategy can elicit more potent immune responses than conventional subcutaneous needle injection and has been demonstrated to be sufficiently safe.
PittCoVacc has been tested immunogenicity in mice with the emergence of substantial SARS-CoV-2 antibodies within 2 weeks after prime immunization. The research team hoped to test PittCoVacc in humans in clinical trials in the next few months (Table 1) (ScienceDaily, 2020).
The US-based company Novavax has identified a vaccine candidate NVX-CoV2373, a stable, prefusion protein developed through the advanced nanoparticle technology (Table 1 and Fig. 3). The Matrix-M adjuvant will be incorporated with NVX-CoV2373 to enhance immune responses and stimulate increased levels of neutralizing antibodies (Novavax, 2020). A first-in-human trial will be started in May 2020.
Other types of vaccines (e.g., DNA, RNA, vector, whole-cell killed and live-attenuated vaccines) are in the rapid development process (Routley, 2020). A phase 1 study of the novel DNA vaccine INO-4800 (NCT04336410) is underway (Inovio, 2020).
Despite the seriousness of the pandemic ravaging the world, researchers should take the time to assess the safety and efficacy of vaccines in animal models and then conduct related human clinical trials to prevent more harm than good from occurring with hastily produced vaccines.
More information: Feng-Cai Zhu et al. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: a dose-escalation, open-label, non-randomised, first-in-human trial. The Lancet. May 22, 2020 DOI: doi.org/10.1016/S0140-6736(20)31208-3
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