During the first few months of the Coronavirus Disease 2019 (COVID-19) pandemic, the repurposing and development of therapeutic agents has been a major focus of pharmaceutical and clinical research. As the COVID-19 data are continuously evolving and published daily, a list of dynamic resources regarding therapeutic options and public health considerations are provided in Table 1.^1-7 Beyond the need for a treatment for this disease, there is also a pressing need for a Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccine.⁸ With the availability of a SARS-CoV-2 vaccine, there is a greater likelihood of large gatherings and all sectors of the economy re-opening in Illinois^.9 

In addition to COVID-19 treatments, data are also continuously published surrounding SARS-CoV-2 vaccine candidates. Many vaccine developers are taking the “science by press release” tactic of presenting preliminary, unpublished findings to generate public and economic optimism. This may make it difficult for clinicians to parse through substantive clinical evidence.¹⁰ This is compounded with the surge of pre-print publications that obscure the understanding of the current vaccine landscape. This article will review the foundational steps and innovations in SARS-CoV-2 vaccine development, as well as review available data from two vaccine candidates currently in clinical trials.

To understand the processes of creating a SARS-CoV-2 vaccine, the virology, immunopathology, and methods for enhancing the immunologic response to this virus must be considered. SARS-CoV-2 enters human cells using angiotensin-converting enzyme (ACE-2) receptors expressed in nasal mucosa, bronchi, and alveolar epithelium, as well as in extrapulmonary tissues such as the kidney, stomach, bladder, and ileum.¹¹ Specifically, the spike (S) glycoprotein found on the outer surface of the virus (Figure 1) exhibits high affinity for human ACE-2 receptors and is responsible for binding, thus allowing virus entry and replication.^12,13 The S glycoprotein provides novel major antigenic determinants specific to SARS-CoV-2 and is immunodominant, leading to the production of primarily neutralizing antibodies.^14,15,16 These neutralizing antibodies against the receptor binding domain (RBD) of the S protein have been found to be virus-specific inhibitors and are of major interest in vaccine development.¹⁷

Enhancing immunologic response to SARS-CoV-2 can be achieved through various design pathways, including virus-based vaccines, viral vector vaccines, nucleic-acid vaccines, and protein-based vaccines.¹⁸  As of June 9, 2020, there are a total of 10 vaccine candidates undergoing Phase I or Phase II clinical trials. Four of these are inactivated virus vaccines, one is a recombinant protein subunit vaccine, three are nucleic acid vaccines (two RNA and one DNA), and two are non-replicating viral vector vaccines, both using adenovirus as a vector (Table 2).¹⁹ The two that will be discussed in detail will be CanSino’s non-replicating adenovirus type 5 (Ad5) vector vaccine and Moderna’s lipid nanoparticle (LNP) encapsulated mRNA vaccine.

CanSino Biologics, based in China, is currently in Phase II trials with their non-replicating Ad5 vectored SARS-CoV-2 vaccine.²⁰ Adenovirus serves as an attractive vaccine vector for several reasons, including its ability to infect both dividing and non-dividing cells, physical and genetic stability,  and potential for eliciting strong immune responses. It also has a preference for targeting epithelial cells, which can lead to stimulation of both mucosal and systemic immunity. Some disadvantages include poor immunogenicity in those with prior immunity to adenovirus, and the need for high vaccine doses to elicit an immune response.^18,21-23 

CanSino’s Phase I trial, recently published in Lancet, explored the safety, tolerability, and immunogenicity of the Ad5 vaccine in subjects in Wuhan, China.²⁴ A total of 108 subjects who had no evidence of COVID-19 infection received one intramuscular injection of low, medium, or high-dose Ad5 vaccine. Adverse events were reported in 30/36 subjects (83%) in the low and medium dose groups and 27/36 subjects (75%) in the high-dose group. Injection site pain occurred in 58 (54%), fever in 50 (46%), fatigue in 47 (44%), headache in 42 (39%), and muscle pain in 18 (17%) recipients. In the high-dose group, 6 subjects (17%) experienced grade 3 adverse events that limited activity in the first 7 days after injection, compared with 2 subjects (6%) in each the low and medium dose groups. T-cell responses peaked at 14 days post-vaccination and antibody responses peaked at day 28, although follow-up ended at day 28. A four-fold increase in antibodies to the receptor-binding domain was demonstrated in 94-100% of patients, and a four-fold increase of antibodies to live-virus in 50-75% of patients. Notably, adults > 60 years old were excluded and only 16% of participants were > 50 years old.  The authors concluded that this Ad5 vectored vaccine was tolerable and immunogenic in healthy adults.26 As the company proceeds with their Phase II trial, areas of interest will be evaluating the immunogenicity in older patients more susceptible to severe COVID-19 disease, vaccine durability past 28 days, and further assessing adverse events in a larger, older study population.

Perhaps the vaccine that is garnering the most interest is the mRNA-1273 vaccine currently being developed by Moderna and the National Institute for Allergy and Infectious Diseases (NIAID).²⁵ This vaccine is an LNP-encapsulated mRNA vaccine expressing a prefusion-stabilized S protein. Advantages of this novel mRNA design include flexible antigen manipulation, high potency (which may confer strong CD4+ and CD8+ responses with one or two doses), and the potential for rapid, cost-effective, large-scale production (Figure 2). Additionally, the lack of viral components will allow production of this vaccine without growing live, highly pathogenic organisms which decreases the risk of contamination or infectious release of SARS-CoV-2 and potential use in bioterrorism. Possible concerns include severe local and systemic inflammatory responses, as well as issues related to stability and RNA degradation which will need to be addressed (e.g., utilizing lipid nanoparticles) in order to take advantage of the quick and efficient in vitro mRNA replication process.^25-28

Moderna provided preliminary data on May 18, 2020. The press release provided immunogenicity data for participants receiving two doses of 25 mcg or 100 mcg and only after the first dose of 250 mcg (n = 15 in each cohort). All subjects achieved seroconversion after one dose, and for the 25 mcg and 100 mcg doses, binding antibody levels were similar to those seen in convalescent sera.  Eight participants in the 25 mcg and 100 mcg cohorts achieved serum neutralizing antibody titers at or above levels seen in convalescent sera. Three patients in the 250 mcg cohort experienced grade 3 adverse events after the second dose, which were transient and self-resolving. One grade 3 adverse event of erythema around the injection site occurred in one participant in the 100 mcg group. Zero adverse events occurred in participants in the 25 mcg cohort.²⁹ The mRNA-1273 vaccine is currently undergoing Phase II trials comparing 50 mcg and 100 mcg doses with an estimated enrollment of 600 participants.³⁰ A recent press release from Moderna stated that Phase III trials are expected to begin in July and that the study protocol has been finalized. The trial will be a randomized 1:1 (100 mcg dose vs. placebo) trial with an expected enrollment of 30,000 United States participants and a primary endpoint of the prevention of symptomatic COVID-19 infection.³¹ 

There are many questions regarding these vaccines that will need to be addressed through clinical trials and long-term follow-up. What is the vaccine effectiveness and durability? Are there any concerns for short and long-term safety particularly with newer vaccine technologies? With the variability seen in patient responses to COVID-19, how will this translate to prevention variability among different demographics, especially in the elderly? How will the vaccine overcome antigenic drift and shift of SARS-CoV-2? What will the role of herd immunity and vaccination rates play in preventing COVID-19 in the future? The successful availability, stability, and distribution of these vaccines will preclude many of these questions. It will only be once a successful vaccine is approved and marketed that we will be able to see its true effect on the population, hopefully leading to an effective post-pandemic reality. ■

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