Lead SARS-CoV-2 Candidate Vaccines: Expectations from Phase III Trials and Recommendations Post-Vaccine Approval
- Elicit long-lasting protective immune responses;
- Should be given to everyone regardless of comorbidity or age, immune status, pregnancy/breastfeeding status;
- Lack the potential to cause antibody dependent enhancement (ADE) or pulmonary immunopathology;
- Should be thermostable in order to enable transportation and storage in developing countries with poor refrigeration facilities;
- Be highly immunogenic in the general population including a population with pre-existing anti-vector antibodies.
2. SARS-CoV-2 Candidate Vaccines with Approved EUA
2.1. The BNT162b2 Vaccine
- We do not know whether NGMATs in children (12–17 year) and adults (18–65 years) are similar to those of older adults (>65 years old). It is also not clear whether the vaccine will be tested in children <12 years old.
- We do not know the NGMAT beyond one week after the second immunization; this is very important because in phase I trial, there was a slight reduction in NGMAT, two weeks after the second immunization .
- The proportion of participants in the whole trial that were used to assess the efficacy of >94% is not known.
- It is not clear whether the 162 cases of COVID-19 (and 9 severe cases) detected in the placebo group were within a certain age group, race/ethnicity, or had prior SARS-CoV-2 infection.
- It is not clear whether the vaccine was tested in participants with comorbidities, which is a group in dire need of a COVID-19 vaccine.
2.2. The mRNA-1273 Vaccine
- We do not know whether the participants in the vaccine group who had COVID-19 or severe cases of the disease had lower NGMATs compared to those that did not have the disease. Thus, data comparing NGMAT in these two groups are warranted. It would also be nice to know the percentage of adults, 18–55 years old, in the vaccine group that had COVID-19 compared to older adults, 56–70 years old. This is very important because in phase I trial, NGMAT in older adults (immunized with same dose of antigen/schedule as in phase II/III) seemed to be slightly higher (878)  compared to those in 18–55 years old (654.3) .
- We do not know what percentage of participants with comorbidities had COVID-19 (if any) in the vaccine group.
- Data on the percentage of individuals that were seropositive, for SARS-CoV-2, after the second dose are not known. This information is very important because it will shed light on how many participants within a group (population) will respond, immunogenically, to the vaccine.
- We do not know whether the NGMAT will change three weeks (and beyond) after the second immunization and/or whether the number of COVID-19 cases in the vaccine group will increase. So far, we have data only on the number of COVID-19 cases, two weeks after the second dose.
- The proportion of participants in the whole trial that were used to assess the efficacy of 94.5% is not known. A larger proportion size will reflect reliable data and vice versa.
- Although the study included participants from diverse racial/ethnic backgrounds, the study was conducted only in one country (the U.S.) and did not include children and young adults < 18 years old. Data from other geographic regions around the world and from an age group < 18 years are needed.
3. SARS-CoV-2 Candidate Vaccines in Phase II/III Trials
3.1. Inactivated SARS-CoV-2 Vaccines
- Data showing NGMAT in individuals with comorbidities and from different ethnic/racial backgrounds; the phase II trial was conducted only on a healthy group of participants and the ongoing phase III trial (Table 1) excludes individuals with an immunodeficient immune system. Thus, it is not clear how individuals with comorbidities (in dire need of SARS-CoV-2 vaccine) or patients with a compromised immune system will respond to CoronaVac.
- Data showing NGMATs in different age groups. It is not clear whether the immunogenicity of CoronaVac decreases with age as has been observed with other SARS-CoV-2 candidate vaccines [31,33,35,44,45]. In other words, do older adults (50–59 years old) mount a lower response to the vaccine compared to younger adults (18–29 years old)?
- Data demonstrating the immunogenicity of the vaccine in older adults (>60 years, who are in dire need of a SARS-CoV-2 vaccine). We do not know how immunogenic the vaccine will be in people in this age group. If immune responses in the 50–59 years old group are lower than those in the 18–29 years old group, a dose of more than 6 μg/dose of CoronaVac may be required to elicit a strong immune response in adults who are >60 years old. Thus, in phase III trial, the first priority should evaluate 6 μg dose (instead of 3 μg as indicated in Zhang et al., ), at 28 days schedule, given the fact that this dose had minor adverse effects (e.g., pain at injection site), which were not different from the 3 μg dose.
- Data showing the longevity of neutralizing antibody titers beyond 28 days; phase II neutralizing antibody titers were conducted using sera collected 28 days (after the second dose). Thus, it is not clear how long the neutralizing antibody titers will last.
- Assess the efficacy and safety of the vaccine in an age group, which is 9–17 years old. As mentioned above, CoronaVac is an inactivated vaccine formulated with the adjuvant, aluminum hydroxide; unfortunately, some inactivated viral vaccines against respiratory diseases (e.g., respiratory syncytia virus ) formulated with aluminum adjuvant have been associated, in a few cases, with vaccine-associated enhanced viral disease such as pulmonary immunopathology. Although pulmonary immunopathology, in non-human primates or human primates, has not been reported for CoronaVac or any SARS-CoV-2 vaccine, it has been reported in preclinical studies with SARS-CoV and MERS .
- Assess the potential for long-term adverse effect(s). Preclinical studies in non-human primates did not show that CoronaVac can promote ADE . However, it is not known whether the same will be true once antibody titers wane.
- Determine whether the NGMATs (44.1 and 65.4) elicited by the vaccine will offer efficient protection. Preclinical studies of the vaccine with non-human primates showed that a lower NGMAT (of 24) offers complete protection from SARS-CoV-2 infection ; however, the titers in clinical trials (44.1 and 65.4) are lower than those in convalescent sera from patients who have recovered from COVID-19 (with NGMAT of at least 70) [33,49,50].
- Data showing the efficacy of the vaccine in a larger number of participants. Phase II trials were conducted only with 600 participants, which is a very small proportion of the general population.
3.1.2. Inactivated SARS-CoV-2 and BBIBP-CorV
3.2. Replication Deficient Vector Vaccines
3.2.1. Ad5 nCoV
3.2.2. Sputnik V (Gam-COVID-Vac)
- Determine the efficacy of the vaccine in a group with high (>200) pre-existing anti-Ad26 and Ad5-neutralizing antibody titers. Phase I/II studies were conducted in participants with low pre-existing anti-Ad-neutralizing antibody titers (~25); 43–67% of people in some African countries, ~54% in Thailand, and 5.4–17.8% of people in other regions around the world have pre-existing anti-Ad26 antibodies . It is worth noting that some of these people have neutralizing antibody titers of 200–1000.
- It is also recommended that a larger number of participants be included in future studies as well as a control or placebo group; phase I/II studies did not have a control group and the number of participants were very low.
- Assess the efficacy and safety of the vaccine in other age groups, <18 years and >60 years.
3.2.3. ChAdOx1 nCoV-19
- Assess the efficacy of the vaccine in a population that has high levels (>200) of pre-existing anti-ChAdOx1-neutralizing antibody titers. In a phase I/II trial, only one participant had high levels (>200) of pre-existing anti-ChAdOx1-neutralizing antibody titers. Pre-existing antibodies against chimpanzee adenoviruses in the western world are very low and may not affect the efficacy of the vaccine. However, in countries (especially African countries) with natural habitats for chimpanzee, pre-existing antibodies against chimpanzee adenoviruses are high in the human population [56,57]. Thus, the efficacy of the vaccine in this group of individuals is warranted.
- Assess the efficacy of ChAdOx1 nCoV-19 vaccine in age groups, <18 years and >56 years.
3.2.4. Ad26.COV2.S (JNJ-78436735 or Ad26COVS1)
- Assess the efficacy of the vaccine in a population that has high levels (>200) of pre-existing anti-Ad26-neutralizing antibody titers. Seropositivity/titers for Ad26 vector in participants were not reported and thus it is difficult to assess whether the vaccine will be immunogenic in a population with high titer anti-Ad26-neutralizing antibodies.
- It is recommended that a larger number of participants, especially individuals ≥65 years old, be included in future studies.
3.3. Recombinant Protein Vaccine
4. Outlook and Perspectives for the Future
5. Limitations in Efficacy Data between Vaccine Trials
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
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|Developer||Vaccine Name (Component)||Storage|
|Required Doses||Weeks Apart||Age |
|Exclusion Criteria from Studies||Clinical Trial Registration Numbers|
|Sinovac||CoronaVac (inactivated SARS-CoV-2 in aluminum hydroxide adjuvant)||2–8 °C||2x: 600 SU/dose *||2 and 4||18–59||-History of COVID-19 or presence of SARS-CoV-2 antibodies|
-Used immunosuppressive agents within 6 months
|Sinopharm||Inactivated SARS-CoV-2 (inactivated SARS-CoV-2, strain WIV04, in aluminum hydroxide adjuvant)||2–8 °C||2x (dosage not provided)||3||≥18–85||-History of SARS-CoV-2, SARS-CoV or MERS-CoV infections|
-Received other investigational CoV vaccines (SARS-CoV and MERS-CoV)
-Receiving anti-TB therapy
|BBIBP-CorV (inactivated SARS-CoV-2, strain HB02, in aluminum hydroxide adjuvant)|
|Bharat Biotech||BBV152 (inactivated SARS-CoV-2 in aluminum hydroxide gel—imidazoquinoline adjuvant)||2–8 °C||2x: 6 μg/dose||4||≥18||-History of SARS-CoV infection|
-History of COVID-19 investigational or licensed vaccination
-Pregnant/breastfeeding -Immunodeficient (HIV)
-Hepatitis B or C infection
|Replication Deficient Vector Vaccines|
|CanSino||Ad5 nCoV % (replication-deficient Ad type 5 vector expressing full-length spike protein)||2–8 °C||1x (VP not provided) **||N/A||≥18||-History of COVID-19 or presence of SARS-CoV-2 antibodies|
-Pregnant/breastfeeding -Using immunosuppressive agents or immunodeficient
-Adenovirus vectored vaccines
|Gamaleya National Center of Epidemiology and Microbiology||Sputnik V €,# or Gam-COVID-Vac (combined replication-deficient Ad types 5 and 26 vectors each expressing full-length spike protein)||Frozen version |
(−18 °C) and lyophilized version
|2x (prime with rAd26-S and boost with rAd5-S): VP dosage not provided ***||3||≥18||-History of COVID-19 or presence of SARS-CoV-2 antibodies|
-Immunosuppressive agents within 3 months
|AstraZeneca||ChAdOx1 nCoV-19 (replication-deficient Ad type 5 vector expressing full-length spike protein)||2–8 °C||1x: 5 × 1010 VP|
2x: 5 × 1010 VP and 3.5–6.5 × 1010 VP
|-History of COVID-19 or presence of SARS-CoV-2 antibodies|
|Johnson & Johnson/Janssen Pharma||Ad26.COV2.S or JNJ-78436735|
(replication-deficient Ad-type 26 vector expressing full-length spike protein)
|2–8 °C||1x: 5 × 1010 VP||N/A||≥18||-Previous vaccination with CoV vaccine|
-Received investigational adenoviral-vectored vaccines within 6 months
|Moderna||mRNA-1273 ∑ (mRNA of full-length spike protein in a lipid nanoparticle)||Frozen between −25 and −15 °C||2x: 100 μg each||4||≥18||-History of SARS-CoV-2 infection|
-Received other investigational CoV vaccines (SARS-CoV and MERS-CoV)
-Received systemic Immunosuppressants for >14 days within 6 months
|Pfizer and BioNTech||BNT162b2 ∑ (mRNA of full-length spike protein in a lipid nanoparticle)||Frozen at −70 °C ± 10 °C||2x: 30 μg each||3||≥12||-Symptoms/diagnosis of COVID 19 by NAAT $|
-Previous vaccination with CoV vaccine
Note: Positive serological test for SARS-CoV-2 was not excluded
|Recombinant Protein Vaccine|
|Novavax||NVX-CoV2373 (a “nanoparticle” of trimeric full-length recombinant spike protein formulated in Matrix-M1 adjuvant)||2–8 °C||2x: 5 µg SARS-CoV-2 rS + 50 µg Matrix-M1 adjuvant/dose||3||18–84||-History of COVID-19 or presence of SARS-CoV-2 antibodies|
-Pregnant/breastfeeding -Immunosuppressive or immunodeficient status
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Tumban, E. Lead SARS-CoV-2 Candidate Vaccines: Expectations from Phase III Trials and Recommendations Post-Vaccine Approval. Viruses 2021, 13, 54. https://doi.org/10.3390/v13010054
Tumban E. Lead SARS-CoV-2 Candidate Vaccines: Expectations from Phase III Trials and Recommendations Post-Vaccine Approval. Viruses. 2021; 13(1):54. https://doi.org/10.3390/v13010054Chicago/Turabian Style
Tumban, Ebenezer. 2021. "Lead SARS-CoV-2 Candidate Vaccines: Expectations from Phase III Trials and Recommendations Post-Vaccine Approval" Viruses 13, no. 1: 54. https://doi.org/10.3390/v13010054