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Developing a low-cost and accessible
COVID-19 vaccine for global health
Peter J. HotezID
1,2,3,4
*, Maria Elena BottazziID
1,2
*
1Texas Children’s Center for Vaccine Development, Departments of Pediatrics and Molecular Virology and
Microbiology, National School of Tropical Medicine, Baylor College of Medicine, Houston, Texas, United
States of America, 2Department of Biology, Baylor University, Waco, Texas, United States of America,
3Hagler Institute for Advanced Study at Texas A&M University, and Scowcroft Institute of International
Affairs, Bush School of Government and Public Service, Texas A&M University, College Station, Texas,
United States of America, 4James A. Baker III Institute of Public Policy, Rice University, Houston, Texas,
United States of America
*hotez@bcm.edu (PJH); bottazzi@bcm.edu (MEB)
Overview
There is an urgent need to advance safe and affordable COVID-19 vaccines for low- and mid-
dle-income countries of Asia, Africa, and Latin America. Such vaccines rely on proven tech-
nologies such as recombinant protein–based vaccines to facilitate its transfer for emerging
market vaccine manufacturers. Our group is developing a two-pronged approach to advance
recombinant protein–based vaccines to prevent COVID-19 caused by SARS-CoV-2 and other
coronavirus infections. One vaccine is based on a yeast-derived (Pichia pastoris) recombinant
protein comprised of the receptor-binding domain (RBD) of the SARS-CoV formulated on
alum and referred to as the CoV RBD219-N1 Vaccine. Potentially, this vaccine could be used
as a heterologous vaccine against COVID-19. A second vaccine specific for COVID-19 is also
being advanced using the corresponding RBD of SARS-CoV-2. The first antigen has already
undergone current Good Manufacturing Practices (cGMP) manufacture and is therefore
“shovel ready” for advancing into clinical trials, following vialing and required Good Labora-
tory Practice (GLP) toxicology testing. Evidence for its potential efficacy to cross-protect
against SARS-CoV-2 includes cross-neutralization and binding studies using polyclonal and
monoclonal antibodies. Evidence in support of its safety profile include our internal assess-
ments in a mouse challenge model using a lethal mouse-adapted SARS strain, which shows
that SARS-CoV RBD219-N1 (when adsorbed to aluminum hydroxide) does not elicit eosino-
philic lung pathology. Together, these findings suggest that recombinant protein–based vac-
cines based on the RBD warrant further development to prevent SARS, COVID-19, or other
coronaviruses of pandemic potential.
“The thing we have to think about now that’s different is,how do we produce vaccines specifi-
cally for the developing world if this is a truly global epidemic.”—Seth Berkley,CEO,Gavi
Introduction: Disease burden in low- and middle-income countries
As of June 2020, COVID-19 caused by the SARS-CoV-2 coronavirus has infected more than 7
million people globally (confirmed cases) and caused almost 400,000 deaths [1]. Although the
epidemic began in China, Europe, and the United States, there are significant concerns about
the risks of disease emergence in low- and middle-income nations. There are now more almost
750,000 cases in Brazil, 300,000 cases in India, and 50,000 cases in South Africa, such that
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OPEN ACCESS
Citation: Hotez PJ, Bottazzi ME (2020) Developing
a low-cost and accessible COVID-19 vaccine for
global health. PLoS Negl Trop Dis 14(7):
e0008548. https://doi.org/10.1371/journal.
pntd.0008548
Editor: Gregory Gromowski, WRAIR, UNITED
STATES
Published: July 29, 2020
Copyright: ©2020 Hotez, Bottazzi. This is an open
access article distributed under the terms of the
Creative Commons Attribution License, which
permits unrestricted use, distribution, and
reproduction in any medium, provided the original
author and source are credited.
Funding: The authors received no specific funding
for this work.
Competing interests: I have read the journal’s
policy and the authors of this manuscript have the
following competing interests: The authors have
developed subunit vaccines against SARS and
MERS coronavirus infections. They are involved in
the process of developing a vaccine against SARS-
CoV-2.
COVID-19 will become widespread among the poor living in the group of 20 nations [1,2].
Moreover, SARS-CoV-2 infection is expected to emerge in the Global South [3]. In the African
region of the World Health Organization (WHO), COVID-19 is now spreading in the popu-
lated areas of Ghana, Nigeria, and Democratic Republic of Congo, and presumably across the
region [1]. In nations such as India, for example, the feasibility of enforcing social distancing
in large and crowded urban centers will be particularly daunting [3], so that ensuring access to
a safe and affordable COVID-19 vaccine will become a global priority. Dr. Seth Berkley, the
CEO of Gavi, the Vaccine Alliance, has highlighted the importance of prioritizing a COVID-
19 vaccine specifically for these countries [4].
Rationale and approach
At least a dozen COVID-19 candidate vaccines are under development using different technol-
ogy platforms [5], with an emphasis on speed, maximizing safety, and avoiding vaccine-
induced immunopathology [6]. Many of these will enlist cutting-edge nucleic acid delivery
technologies and other innovative approaches. In the meantime, there is urgency to address
and rapidly respond to Gavi’s charge and pursue safe, low-cost, easily administered, and rap-
idly scalable approaches. For instance, Texas Children’s Center for Vaccine Development
(CVD) at Baylor College of Medicine, in collaboration with its nonprofit product development
partners—Seattle-based PATH and Infectious Disease Research Institute (IDRI)—have been
spearheading a coronavirus vaccine program focusing on recombinant subunit protein vac-
cines produced in a globally available microbial fermentation platform, and optimized to max-
imize yield following expression and protein purification [7,8].
Towards this goal, we are now also developing the SARS-CoV-2 RBD recombinant protein
as a potential vaccine candidate, in parallel with the existing CoV RBD219-N1 candidate vac-
cine, which was previously developed and manufactured under cGMP in 2016 [710]. The
bulk drug substance has been stored frozen (70˚C to 80˚C) and remains stable through ongo-
ing testing. Furthermore, an independent quality assessment confirmed the suitability of the
material through Phase 2 clinical trials.
Both RBD vaccine candidates have potential as vaccine antigens to prevent SARS-CoV-2
infection and/or COVID-19. Overall, our initial approach relies on advancing the already
manufactured CoV RBD219-N1 as a heterologous recombinant subunit vaccine to protect
against both SARS and COVID-19 [9], and in parallel accelerate the advancement of the
SARS-CoV-2 RBD candidate as a homologous COVID-19 vaccine (Fig 1). Our preliminary
studies now show that the SARS-CoV-2 RBD candidate, which is specific for the sequence of
the SARS-CoV-2, can also be highly produced in the yeast P.pastoris. Both approaches rein-
force each other, as the processes developed for the CoV RBD219-N1 candidate also apply to
the SARS-CoV-2 candidate, and both antigens downstream could be further developed as
potentially a bivalent or a universal coronavirus vaccine.
The SARS-CoV protein known as CoV RBD219-N1 was selected on its ability to elicit high
titers of neutralizing antibodies against both SARS-CoV pseudotype virus and live SARS-CoV
virus [7,8], prior to confirmatory testing against SARS-CoV challenge in animal models. It also
induced high-level neutralizing antibodies and protective immunity with minimal immunopa-
thology in mice after a homologous virus challenge with SARS-CoV (MA15 strain) [9,10].
There are several advantages of the CoV RBD candidate antigens and vaccines for purposes
of global health:
1. High yield and low cost. The antigens are expressed in P.pastoris, a low-cost expression
platform, which can be produced and scaled at high yields [7,8]. By deleting an N-linked
glycosylated asparagine at the N-1 position of RBD219, both the yield and antigenicity
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improved. At a 10-liter scale production process, the CoV RBD219-N1 antigen was pro-
duced through fermentation at 400 mg/L fermentation supernatant (FS) with purification
recovery >50% [7,8]. A panel of characterization tests indicates that the process is repro-
ducible and robust and that the purified, tag-free RBD219-N1 protein has high purity and a
well-defined structure. It is therefore suitable for both pilot scale manufacturing and for
transition into process improvements leading to industrial scale manufacturing.
2. Technology transfer. The process is suitable for technology transfer to emerging market
vaccine manufacturers (aka DCVMs, developing country vaccine manufacturers) having
expertise in fermentation technology (https://www.dcvmn.org/) [11]. The P.pastoris
derived recombinant protein is currently produced by several DCVMs, including those in
Bangladesh, Brazil, Cuba, India, and Indonesia.
3. Shovel ready. The CoV RBD219-N1 antigen was manufactured under cGMP and can be
vialed to produce between 20,000 and 200,000 doses, with the possibility of transferring
production processes and cell banks to DCVMs for large-scale production sufficient to
meet global needs.
Beyond low cost and ease of potential technology transfer to DCVMs, an advantage of
employing a recombinant protein subunit vaccine is the long-standing safety record of this class
of vaccines, and the fact that this technology has been used for the licensure of two other antivi-
ral vaccines—hepatitis B and human papillomavirus, as well as biologics (e.g., insulin) [11].
Safety evaluation of a low-cost recombinant vaccine
In addition to their low cost and suitability for use in public immunization programs in low-
and middle-income countries, we pursued RBD recombinant protein–based vaccines as a
Fig 1. Estimated timelines of coronavirus RBDs as COVID-19 vaccines. cGMP, current good manufacturing practices; RBD, receptor-binding domain.
https://doi.org/10.1371/journal.pntd.0008548.g001
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technology to maximize safety relative to other platforms, such as virus vectors that have previ-
ously been found to induce immune enhancement. For instance, immune enhancement in
children following a formalin-inactivated respiratory syncytial virus (RSV) vaccine was first
reported in the 1960s and later shown to occur in laboratory animals with early prototype
SARS-CoV vaccines using virus-vectored platforms or inactivated virus constructs [12]. We
have recently summarized the major safety concerns of some prototype coronavirus vaccines
based on studies conducted in laboratory animals (rodents, ferrets, and nonhuman primates)
[12]. They include the following points.
Avoiding virus-vectored platforms
Some of the earliest SARS-CoV vaccine candidates used vectored-based platforms, and these
were associated with immune enhancement or activation. In 2004–2005, scientists at the Pub-
lic Health Agency of Canada’s National Microbiology Laboratory in Winnipeg, Manitoba
(who helped to develop the first successful Ebola vaccine), found that a recombinant modified
vaccinia Ankara (rMVA) expressing the S-spike protein resulted in severe liver pathology
upon SARS-CoV virus challenge. Similarly, rMVA expressing the S-spike also resulted in lung
immunopathology in rhesus macaques, as did other virus-vectored constructs. Lung immuno-
pathology is also linked to whole inactivated viral vaccines. However, it was determined that in
many cases eosinophilic pathology is driven by the SARS nucleocapsid (N) protein, although a
recent trial in nonhuman primates found that an alum-adjuvanted inactivated SARS-CoV-2
vaccine did not induce immunopathology [13]. Among the major conclusions of these studies
was that they may be driven by T helper-17 (Th17) responses linked to interleukin-6 [12,14],
and that aluminum formulations exhibit greatly reduced immunopathology [15].
Recombinant protein RBD vaccines
Given the history of virus-vector platforms and inactivated vaccines in eliciting eosinophilic
immunopathology, our emphasis has been on the evaluation of inexpensive recombinant pro-
teins produced in microbial systems. These are comprised of the CoV RBD219-N1 antigen,
encoding amino acids 319–536 (219 AA) of the SARS-CoV S-spike protein [710], and now a
second, CoV2 RBD antigen, which is also expressed without the N-terminal amino acid. The
rationale for selecting the RBD domain of the S protein includes focusing on the key compo-
nent that binds to the human angiotensin converting enzyme 2 (ACE2) receptor, and remov-
ing the known elements of the S protein involved in immune enhancement. Supporting
studies summarized elsewhere emphasize how S protein peptides outside of the RBD can
induce immune enhancement in non-human primates [12]. Moreover, CoV RBD219-N1
induce high titers of neutralizing antibodies in mice and 100% infection against SARS CoV
virus challenge [10]. Alum formulations of CoV RBD 219-N1 do not induce immunopathol-
ogy [10], a finding consistent with other published studies [1315].
Evaluating efficacy
There is evidence to justify advancing the CoV RBD219-N1 antigen as either a homologous
vaccine against SARS [710] or as a heterologous vaccine against COVID-19 [9]. In parallel, a
CoV2 RBD protein candidate is being advanced. Regarding the former, against SARS CoV
homologous virus challenge the vaccine formulated on alum exhibits high levels of protective
immunity and with evidence of minimal or no immune enhancement [10]. With regards to
cross-protection against SARS CoV2, the RBD of the SARS-CoV-2 and CoV RBD219-N1
share significant similarity of amino acid sequence (>75% identity, >80% similarity) and
there is evidence that both viruses use the human ACE2 receptor for cell entry [9]. Further
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published studies indicate strong antigenic similarities between the SARS-CoV and SARS-
CoV-2 RBDs, and the potential for cross protection. For example, serum from a convalescent
SARS-CoV patient was shown to neutralize SARS-CoV-2 driven entry [16]. Moreover, new
studies by Tai and colleagues find that using pseudotyped SARS-CoV-2, the SARS-CoV RBD
blocks the entry of both SARS-CoV and SARS-CoV-2 pseudovirus into human ACE2-expres-
sing 293T cells [17]. Through pseudovirus neutralization activity, it was found that SARS-CoV
RBD-specific antisera could neutralize SARS-CoV-2 pseudovirus infection, suggesting that
SARS-CoV RBD-specific antibodies can cross-react with SARS-CoV-2 RBD and cross neutral-
ize SARS-CoV-2 pseudovirus infection [17]. Additional studies find that multiple (but not all)
neutralizing monoclonal antibodies bind to both RBDs [9,18,19].
Next steps
An international priority is the scale-up and global access of an affordable and safe recombi-
nant vaccine to prevent emerging coronavirus infections, including COVID-19. Our aspira-
tional goal is to protect global populations at risk for this important emerging virus infection.
A low-cost recombinant protein antigen expressed in P.pastoris and formulated on aluminum
or other accessible adjuvants represents a highly accessible technology to transfer to low- and
middle-income countries. It represents one of several key mechanisms for ensuring that popu-
lations across the major affected nations of Africa, Asia, and the Americas will benefit from
COVID-19 vaccinations.
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... The fundamental objective of vaccination is the prevention of pathogenic infections [59]. Obstacles such as budget constraints in providing vaccines to developing countries and resistance from antivaccine groups have impeded progress in this area [60]. Furthermore, intrinsic genetic factors of pathogens, such as mutation rates and adaptability to other hosts, contribute to the complexity of eradication. ...
... Based on Nucleocapsid as Vaccine Candidate. Recombinant protein technology has emerged as an efficient, cost-effective, and widely available approach to facilitate production of recombinant proteins in Journal of Immunology Research various host expression systems, including microbial systems [60]. Several studies have used E. coli to express N proteins and evaluated in animal models [67,68]. ...
... One such development involves glyco-nanoparticles decorated with N antigens, which have shown promising immune responses in murine model [74]. As mentioned before, the principal advantage of proteins vaccines is the production; additionally, protein vaccines are more stable and can be save at 4°C [60]. However, adjuvants are required to improve induce immune responses. ...
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The rampant spread of the COVID-19 infection poses a grave and formidable challenge to global healthcare, with particular concern to the inhabitants of the African continent. In response to these pressing concerns, different strategies have been employed to combat the emergence of this insidious disease, encompassing crucial measures such as physical distancing, the utilization of face masks, meticulous hand hygiene, and widespread vaccination campaigns. Nevertheless, the economic realities faced by numerous African nations, characterized by their classification as “low-income countries (LICs)”, present a formidable barrier to accessing and distributing approved vaccines to their populations. Moreover, it is essential to discuss the hesitancy of the European Union (EU) in releasing intellectual property rights associated with the transfer of vaccine technology to Africa. While the EU has been a key player in global efforts to combat the pandemic, there has been reluctance in sharing valuable knowledge and resources with African countries. This hesitancy raises concerns about equitable vaccine access and the potential for a prolonged health crisis in Africa. This review underscores the urgent imperative and need of establishing localized vaccine development and production facilities within Africa, necessitating the active involvement of governments and collaborative partnerships to achieve this crucial objective. Furthermore, this review advocates for the exploration of viable avenues for the transfer of vaccine technology as a means to facilitate equitable vaccine access across the African continent and also the cruciality and the need for the EU to reconsider its stance and actively engage in transferring vaccine technology to Africa through sharing intellectual property. The EU can contribute to the establishment of localized vaccine production facilities on the continent, which will not only increase vaccine availability but also promote self-sufficiency and resilience in the face of future health emergencies.
... Cytosine-phospho-Guanine (CpG) oligodeoxynucleotides (ODN) are Toll-like receptor (TLR)-9 agonists have been used as adjuvants in approved vaccines to improve protective antibody levels and seroresponse rates for hepatitis B [6], COVID-19 [7], and most recently, anthrax [8]. We hypothesized that the addition of a CpG ODN adjuvant to the Alhydrogel formulation of recombinant Na-GST-1 would result in increased antigen-specific IgG responses compared to the Alhydrogel formulation without CpG, thereby increasing the likelihood of protective efficacy of this product. ...
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Background Recombinant Necator americanus Glutathione-S-Transferase-1 (Na-GST-1) formulated on Alhydrogel (Na-GST-1/Alhydrogel) is being developed to prevent anemia and other complications of N. americanus infection. Antibodies induced by vaccination with recombinant Na-GST-1 are hypothesized to interfere with the blood digestion pathway of adult hookworms in the host. Phase 1 trials have demonstrated the safety of Na-GST-1 formulated on Alhydrogel, but further optimization of the vaccine adjuvant formulation may improve humoral immune responses, thereby increasing the likelihood of vaccine efficacy. Methods A randomized, observer-blind, dose escalation Phase 1 trial was conducted in 24 healthy, hookworm-naïve adults. In each cohort of 12 participants, 4 were randomized to receive 100 µg of Na-GST-1/Alhydrogel and 8 to receive 30 µg or 100 µg of Na-GST-1/Alhydrogel plus the Cytosine-phospho-Guanine (CpG) oligodeoxynucleotide Toll-like receptor-9 agonist, CpG 10104, in the first and second cohorts, respectively. Progression to the second cohort was dependent upon evaluation of 7-day safety data after all participants in the first cohort had received the first dose of vaccine. Three intramuscular injections of study product were administered on days 0, 56, and 112, after which participants were followed for 6 months. IgG and IgG subclass antibody responses to Na-GST-1 were measured by qualified indirect ELISAs at pre- and post-vaccination time points. Results Na-GST-1/Alhydrogel administered with or without CpG 10104 was well-tolerated. The most common solicited adverse events were mild injection site tenderness and pain, and mild headache. There were no vaccine-related serious adverse events or adverse events of special interest. Both dose concentrations of Na-GST-1/Alhydrogel plus CpG 10104 had significantly higher post-vaccination levels of antigen-specific IgG antibody compared to Na-GST-1/Alhydrogel without CpG, starting after the second injection. Peak anti-Na-GST-1 IgG levels were observed between 2 and 4 weeks following the third dose, regardless of Na-GST-1 formulation. IgG levels decreased but remained significantly above baseline in all groups by day 290, at which point all participants (20 of 20 evaluable participants) still had detectable IgG. Longitudinal antigen-specific IgG1 and IgG3 subclass responses mirrored those of total IgG, whereas IgG4 responses were lower in the groups that received the vaccine with the CpG adjuvant compared to the non-CpG group. Conclusions Vaccination of hookworm-naïve adults with Na-GST-1/Alhydrogel plus CpG 10104 was safe and minimally reactogenic. Addition of CpG 10104 to Na-GST-1/Alhydrogel resulted in significant improvement in IgG responses against the vaccine antigen. These promising results have led to inclusion of the CpG 10104 formulation of Na-GST-1/Alhydrogel in a Phase 2 proof-of-concept controlled human infection trial.
... In efforts to tackle the COVID-19 pandemic, recent research highlights the advantages of RBD antigen-based vaccine candidate, 10,11 which offer relatively low-cost production through the P. pastoris expression platform and are relevant for implementation in developing countries, [12][13][14] including Indonesia. Despite their advantages, subunit vaccines like RBD often have low immunogenicity, necessitating the use of adjuvants. ...
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Globally, dozens of COVID-19 vaccines are licensed under emergency or conditional authorization, but especially in low and middle-income countries, their availability varies. Indonesia decided to become independent and produce its own vaccines locally. This study investigated the safety and immunogenicity of a SARS-CoV-2 recombinant protein subunit vaccine adjuvanted with Alum + CpG 1018. This study involved 360 adults aged 18 years and above. It compared two vaccine dosages, a-12.5 µg and a 25-µg dose of receptor binding domain protein, to a placebo (1:1:1). A total of 40.6% of participants in this study experienced at least one adverse event (AE), with most being mild. There was no statistically significant difference in AEs between the groups. The microneutralization test showed the highest neutralizing antibody titer (IU/mL) in the 25 µg dose vaccine group at day 28 after the second dose (3,300 95%CI 2,215-4,914), although it was not statistically different from the 12.5 µg dose group (3,157 95%CI 2,135-4,669). Similarly, IgG antibody concentrations in the 25 µg dose vaccine group at day 28 were the highest compared to the 12.5 µg dose and placebo. According to protocol, only the formulation with the better antibody profile and comparable reactogenicity was further evaluated at months three and six. Thus, follow-up was only performed for the 25 µg dose vaccine, demonstrating antibody persistence at month six and had a favorable safety profile. These results position this SARS-CoV-2 recombinant protein subunit vaccine adjuvanted with Alum + CpG 1018 as a promising candidate to fight against COVID-19.
... Many are confident that it will eventually become better known, and that the public's hesitancy will diminish as time goes on. (Hotez et al. 2020) Inactivated whole virus vaccines were some of the first vaccines ever formulated, having more than 50 years of research done in its name. They are well trusted by both the public and vaccine specialists. ...
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The Coronavirus (COVID-19) is the first major virus to spread across the world and cause a catastrophe in decades. Vaccines are a tried and tested method of preventing the spread of viruses and have hence been used to halt the outbreak. On the surface, many of the vaccines are indistinguishable, prompting the following question: What are the differences between COVID-19 vaccines, and how well can they protect and individual? The objective of this research paper is to reveal the differences between types of COVID-19 vaccines and the processes they use to function. A comparison of each vaccine’s advantages/disadvantages along with an analysis of their efficacies and safety will be used to determine the protective power of each vaccine. This paper will go over four different types of platforms available: mRNA, Recombinant protein, Inactivated Whole Virus and Viral Vector vaccines along with 5 different vaccines: BNT162b2, mRNA-1273, NVX-2373, BBV-152, AD.26.CoV2.S.
... Bio Farma has developed a recombinant protein subunit vaccine (IndoVac) which targets SARS-CoV-2 receptor-binding domain (RBD). The vaccine development was based on similar RBD-based vaccine, which has been manufactured previously in 2016 as a heterologous recombinant subunit vaccine, to provide protection against SARS [2]. Immunogenicity and safety of the vaccine had been evaluated in previous pre-clinical and early clinical phases, showing the vaccine was well-tolerated and elicited good immune response (unpublished data). ...
... Compared with mRNA vaccines-primary SARS-CoV-2 vaccines used globallyrecombinant protein vaccines are more stable and less dependent on the cold chain, making them easier to manufacture and distribute worldwide [22,23]. However, recombinant proteins exhibit poor immunogenicity and require appropriate adjuvants to induce immunity [24]. ...
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The new coronavirus infection causes severe respiratory failure following respiratory tract infection with severe acute respiratory syndrome-related coronavirus (SARS-CoV-2). All currently approved vaccines are administered intramuscularly; however, intranasal administration enhances mucosal immunity, facilitating the production of a less invasive vaccine with fewer adverse events. Herein, a recombinant vaccine combining the SARS-CoV-2 spike protein receptor-binding domain (RBD), or S1 protein, with CpG-deoxyoligonucleotide (ODN) or aluminum hydroxide (alum) adjuvants was administered intranasally or subcutaneously to mice. Serum-specific IgG titers, IgA titers in the alveolar lavage fluid, and neutralizing antibody titers were analyzed. The nasal administration of RBD protein did not increase serum IgG or IgA titers in the alveolar lavage fluid. However, a significant increase in serum IgG was observed in the intranasal group administered with S1 protein with CpG-ODN and the subcutaneous group administered with S1 protein with alum. The IgA and IgG levels increased significantly in the alveolar lavage fluid only after the intranasal administration of the S1 protein with CpG-ODN. The neutralizing antibody titers in serum and bronchoalveolar lavage were significantly higher in the intranasal S1-CpG group than in every other group. Hence, the nasal administration of the S1 protein vaccine with CpG adjuvant might represent an effective vaccine candidate.
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The receptor‐binding domain (RBD) of the SARS‐CoV‐2 virus spike protein has emerged as a promising target for the generation of neutralizing antibodies. Although the RBD subunit is more stable than its encoding mRNA, RBD is poorly immunogenic. It is hypothesized that this limitation can be overcome by sustained coadministration with a more potent and optimized adjuvant than standard adjuvants. One such candidate adjuvant, cGAMP, exhibits promising potency via activation of the antiviral STING pathway. Unfortunately, delivery of cGAMP as a therapeutic exhibits poor performance due to poor pharmacokinetics and pharmacodynamics from rapid excretion and degradation. To overcome these limitations, it is sought to create an artificial immunological niche enabling the slow release of cGAMP and RBD to mimic natural infections in which immune‐activating molecules are colocalized with antigen. Specifically, through coencapsulation of cGAMP and RBD in an injectable polymer‐nanoparticle (PNP) hydrogel, the cGAMP‐adjuvanted hydrogel vaccine elicits more potent, durable, and broad antibody responses with improved neutralization as compared to dose‐matched bolus controls and hydrogel‐based vaccines lacking cGAMP. The cGAMP‐adjuvanted hydrogel platform can be further explored for the delivery of other antigens to enhance immunity against a broad range of pathogens.
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Immunoglobulins have emerged as an important tool in passive immunization for the prevention and treatment of infectious diseases. Immunoglobulins are the proteins produced by B cells that bind to specific pathogens, neutralize them, and facilitate their removal by the immune system. In preventive healthcare, immunoglobulins are used for primordial, primary, secondary, tertiary, and quaternary prevention of infectious diseases. This work was designed to carry out an extensive literature search to provide useful information on immunoglobulins as the tools of passive immunization in preventive healthcare. Relevant and accurate literatures were sourced from the World Health Organization. Centers for Disease Control and Prevention, National Center for Disease Control, PubMed, Scopus, PLoS One, and NATURE journals: Primordial prevention aims to prevent the emergence and spread of risk factors for infectious diseases. Immunoglobulins can be used to prevent the spread of infectious diseases by targeting the pathogens that cause them. The primary prevention aims to prevent the initial infection of individuals at risk of acquiring infectious diseases. Immunoglobulins can be used as prophylaxis to prevent the onset of infection in high-risk individuals. The secondary prevention aims to reduce the severity and duration of infectious diseases. Immunoglobulins can be used to treat infectious diseases and prevent complications. The tertiary prevention aims to prevent the recurrence and complications of infectious diseases. Immunoglobulins can be used to prevent the recurrence of infections in individuals who have already been infected. Quaternary prevention aims to prevent the overuse, misuse, and abuse of medical interventions. Immunoglobulins can be used to prevent the development of antibiotic resistance by reducing the use of antibiotics. However, the use of immunoglobulins in preventive healthcare is not without challenges. The cost-effectiveness of immunoglobulin therapy, long-term safety, and the potential for cross-infection are some of the challenges that need to be addressed. Further research is needed to optimize the use of immunoglobulins in preventive health-care delivery. Immunoglobulins are valuable tools in passive immunization for the prevention and treatment of infectious diseases in preventive healthcare. Their use can help reduce the burden of infectious diseases and improve public health outcomes. Keywords: Immunoglobulins, passive immunization, preventive healthcare.
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We developed a severe acute respiratory syndrome (SARS) subunit recombinant protein vaccine candidate based on a high-yielding, yeast-engineered, receptor-binding domain (RBD219-N1) of the SARS beta-coronavirus (SARS-CoV) spike (S) protein. When formulated with Alhydrogel®, RBD219-N1 induced high-level neutralizing antibodies against both pseudotyped virus and a clinical (mouse-adapted) isolate of SARS-CoV. Here, we report that mice immunized with RBD219-N1/Alhydrogel® were fully protected from lethal SARS-CoV challenge (0% mortality), compared to ~ 30% mortality in mice when immunized with the SARS S protein formulated with Alhydrogel®, and 100% mortality in negative controls. An RBD219-N1 formulation Alhydrogel® was also superior to the S protein, unadjuvanted RBD, and AddaVax (MF59-like adjuvant)-formulated RBD in inducing specific antibodies and preventing cellular infiltrates in the lungs upon SARS-CoV challenge. Specifically, a formulation with a 1:25 ratio of RBD219-N1 to Alhydrogel® provided high neutralizing antibody titers, 100% protection with non-detectable viral loads with minimal or no eosinophilic pulmonary infiltrates. As a result, this vaccine formulation is under consideration for further development against SARS-CoV and other emerging and re-emerging beta-CoVs such as SARS-CoV-2.
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Vaccine candidate tested in monkeys Global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an urgent race to develop a vaccine. Gao et al. report preclinical results of an early vaccine candidate called PiCoVacc, which protected rhesus macaque monkeys against SARS-CoV-2 infection when analyzed in short-term studies. The researchers obtained multiple SARS-CoV-2 strains from 11 hospitalized patients across the world and then chemically inactivated the harmful properties of the virus. Animals were immunized with one of two vaccine doses and then inoculated with SARS-CoV-2. Those that received the lowest dose showed signs of controlling the infection, and those receiving the highest dose appeared more protected and did not have detectable viral loads in the pharynx or lungs at 7 days after infection. The next steps will be testing for safety and efficacy in humans. Science , this issue p. 77
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A SARS-CoV receptor-binding domain (RBD) recombinant protein was developed and manufactured under current good manufacturing practices in 2016. The protein, known as RBD219-N1 when formulated on Alhydrogel®, induced high-level neutralizing antibodies and protective immunity with minimal immunopathology in mice after a homologous virus challenge with SARS-CoV (MA15 strain). We examined published evidence in support of whether the SARS-CoV RBD219-N1 could be repurposed as a heterologous vaccine against Coronavirus Infectious Disease (COVID)-19. Our findings include evidence that convalescent serum from SARS-CoV patients can neutralize SARS-CoV-2. Additionally, a review of published studies using monoclonal antibodies (mAbs) raised against SARS-CoV RBD and that neutralizes the SARS-CoV virus in vitro finds that some of these mAbs bind to the receptor-binding motif (RBM) within the RBD, while others bind to domains outside this region within RBD. This information is relevant and supports the possibility of developing a heterologous SARS-CoV RBD vaccine against COVID-19, especially due to the finding that the overall high amino acid similarity (82%) between SARS-CoV and SARS-CoV-2 spike and RBD domains is not reflected in RBM amino acid similarity (59%). However, the high sequence similarity (94%) in the region outside of RBM offers the potential of conserved neutralizing epitopes between both viruses.
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The outbreak of Coronavirus Disease 2019 (COVID-19) has posed a serious threat to global public health, calling for the development of safe and effective prophylactics and therapeutics against infection of its causative agent, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), also known as 2019 novel coronavirus (2019-nCoV). The CoV spike (S) protein plays the most important roles in viral attachment, fusion and entry, and serves as a target for development of antibodies, entry inhibitors and vaccines. Here, we identified the receptor-binding domain (RBD) in SARS-CoV-2 S protein and found that the RBD protein bound strongly to human and bat angiotensin-converting enzyme 2 (ACE2) receptors. SARS-CoV-2 RBD exhibited significantly higher binding affinity to ACE2 receptor than SARS-CoV RBD and could block the binding and, hence, attachment of SARS-CoV-2 RBD and SARS-CoV RBD to ACE2-expressing cells, thus inhibiting their infection to host cells. SARS-CoV RBD-specific antibodies could cross-react with SARS-CoV-2 RBD protein, and SARS-CoV RBD-induced antisera could cross-neutralize SARS-CoV-2, suggesting the potential to develop SARS-CoV RBD-based vaccines for prevention of SARS-CoV-2 and SARS-CoV infection.
Article
We developed a severe acute respiratory syndrome (SARS) subunit recombinant protein vaccine candidate based on a high-yielding, yeast-engineered, receptor-binding domain (RBD219-N1) of the SARS beta-coronavirus (SARS-CoV) spike (S) protein. When formulated with Alhydrogel®, RBD219-N1 induced high levels of neutralizing antibodies against both pseudotyped virus and a clinical (mouse-adapted) isolate of SARS-CoV. Here, we report that mice immunized with RBD219-N1/Alhydrogel® were fully protected from lethal SARS-CoV challenge (0% mortality), compared to ~30% mortality in mice immunized with the SARS S protein formulated with Alhydrogel®, and 100% mortality in negative controls. An RBD219-N1 formulation with Alhydrogel® was also superior to the S protein, unadjuvanted RBD, and AddaVax (MF59-like adjuvant)-formulated RBD in inducing specific antibodies and preventing cellular infiltrates in the lungs upon SARS-CoV challenge. Specifically, a formulation with a 1:25 ratio of RBD219-N1 to Alhydrogel® provided high neutralizing antibody titers, 100% protection with non-detectable viral loads with minimal or no eosinophilic pulmonary infiltrates. As a result, this vaccine formulation is under consideration for further development against SARS-CoV and potentially other emerging and re-emerging beta-CoVs such as SARS-CoV-2.
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Achieving high levels of neutralizing antibodies to the spike protein of SARS-CoV-2 in a safe manner is likely to be crucial for an effective vaccine. Here, we propose that aluminium-based adjuvants might hold the key to this. Here, Peter Hotez and colleagues discuss the advantages of using an aluminium-based adjuvant in candidate COVID-19 vaccines.
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SARS-CoV-2-caused COVID-19 cases are growing globally, calling for developing effective therapeutics to control the current pandemic. SARS-CoV-2 and SARS-CoV recognize angiotensin-converting enzyme 2 (ACE2) receptor via the receptor-binding domain (RBD). Here, we identified six SARS-CoV RBD-specific neutralizing monoclonal antibodies (nAbs) that cross-reacted with SARS-CoV-2 RBD, two of which, 18F3 and 7B11, neutralized SARS-CoV-2 infection. 18F3 recognized conserved epitopes on SARS-CoV and SARS-CoV-2 RBDs, whereas 7B11 recognized epitopes on SARS-CoV RBD not fully conserved in SARS-CoV-2 RBD. The 18F3-recognizing epitopes on RBD did not overlap with the ACE2-binding sites, whereas those recognized by 7B11 were close to the ACE2-binding sites, explaining why 7B11 could, but 18F3 could not, block SARS-CoV or SARS-CoV-2 RBD binding to ACE2 receptor. Our study provides an alternative approach to prevent SARS-CoV-2 infection using anti-SARS-CoV nAbs.
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Previous work on severe acute respiratory syndrome coronavirus (SARS-CoV) vaccines identified cellular immunopathology and antibody-dependent enhancement as potential safety issues. We discuss the implications of these findings for COVID-19 vaccine development and our approach to optimizing for safety and efficacy. Here, Hotez and colleagues highlight the two ‘faces’ of immune enhancement that could impact COVID-19 vaccine design.
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Increasing evidence points to host Th17 inflammatory responses as contributing to the severe lung pathology and mortality of lower respiratory tract infections from coronaviruses. This includes host inflammatory and cytokine responses to COVID-19 caused by the SARS-2 coronavirus (SARS CoV2). From studies conducted in laboratory animals, there are additional concerns about immune enhancement and the role of potential host immunopathology resulting from experimental human COVID-19 vaccines. Here we summarize evidence suggesting there may be partial overlap between the underlying immunopathologic processes linked to both coronavirus infection and vaccination, and a role for Th17 in immune enhancement and eosinophilic pulmonary immunopathology. Such findings help explain the link between viral-vectored coronavirus vaccines and immune enhancement and its reduction through alum adjuvants. Additional research may also clarify links between COVID-19 pulmonary immunopathology and heart disease.