Vaccines traditionally used are live attenuated viruses, inactivated viruses, protein or polysaccharide conjugated subunit vaccines and virus-like particles. Also, recently included vaccines are nucleic acids, DNA and RNA and viral vectors and recombinant proteins.
SARS-CoV-2 induces a strong adaptive immune response of both T and B cell. Additionally, antibodies IgG and IgM appear about 10 days post-infection. The majority of the patients are able to seroconvert in 3 weeks. The antibodies are created against internal nucleoprotein (N) and spike protein (S) of the virion and possess neutralizing activity. Antibodies which bind to the spike protein, particularly to its receptor-binding domain (RBD), inhibit its attachment to the host cell and counteract the virus [13]. Table 1 lists few vaccine candidates approved through EUA that reached up to or completed Phase 3 trials.
BNT162 vaccine by Pfizer and BioNTech
On December 2, 2020, UK became the first country to approve COVID-19 vaccine BNT162 developed by Pfizer and BioNTech via EUA. On December 11, 2020 US FDA issued first EUA for BNT162 having demonstrated 95% efficacy in preventing disease in phase III clinical trial results [14]. Later Canada and Mexico also approved BNT162 via respective EUA pathways. On December 31, 2020, WHO approved first vaccine candidate, BNT162, for emergency use thereby making it easier to manufacture and distribute this vaccine globally [15]. Initially, four candidates were developed of which two were nucleoside modified mRNA, modRNA; one was uridine containing mRNA, uRNA; and other was self-amplifying mRNA, saRNA. In the preclinical study, modRNA BNT162b2 showed protective antiviral effects in Rhesus macaques with concurrent elevated neutralizing antibody titers and a Th-1 biased cellular response in Rhesus macaques, as well as in mice. Therefore, BNT162b2 was selected for Phase 2/3 clinical trials [16].
In Phase 1/2 trial of two hundred participants aged 18–55 years with a vaccine dose range of 1–100 µg is currently recruiting (NCT04380701) as is a Phase 2/3 trial of about 32,000 participants (NCT04368728) and a Phase 1/2 trial of 160 participants between age 20–85 (NCT04588480) [16].On November 9, 2020, Pfizer and BioNTech declared interim results of 94 participants of Phase 3 trial claiming > 90% efficacy of BNT162b2 against SARS-Cov-2 infection at 7 days after the administration of second dose [16]. Phase 1 trial data showed similar immunogenicity between BNT162b1 and BNT162b2, while BNT162b2 was associated with a lower incidence and severity of systemic reactions than BNT162b1 [17].
Another study of Phase 1/2 data for BNT162b1 (NCT04368728) showed robust immunogenicity at all three doses of 10 µg, 30 µg and 100 µg among 45 participants, 18–55 years of age. Adverse reactions were high at the maximum dose and therefore, participants were not given a second dose. Participants who were given two doses between 1 and 50 µg of BNT162b1 had vigorous receptor-binding domain (RBD)-specific IgG antibody, T-cell and favorable cytokine responses [18].
Both BNT162b1 and BNT162b2 received the FDA Fast Track designation. But BNT162b2 was preferred over BNT162b1 for Phase 2/3 safety study, based on preclinical and clinical study results. The developers have asked the FDA to consider an expanded protocol for the Phase 3 trial to include up to 44,000 participants. Europeans Medicines Agency (EMA) has initiated a rolling review of BNT162b2 which helped to accelerate its approval [16]. One drawback with this vaccine is that it requires storage at − 80° to − 60 °C, a fact that could pose logistic problems [19].
mRNA-1273 vaccine by Moderna
Moderna’s mRNA-1273 becomes the second CVC to be approved by FDA under EUA. It is developed on the basis of available data of coronaviruses causing severe acute respiratory syndrome (SARS) and the Middle East respiratory syndrome (MERS). A Phase 3 trial of 30,000 participants at higher risk for COVID-19 is ongoing. Participants will be given 100 µg dose of mRNA-1273 or placebo and then be followed for up to 24 months (COVE trial; NCT04470427). After successful completion of Phase 1 trial (NCT04283461) of 105 participants, Phase 2 trial of 600 participants evaluating 25 µg, 100 µg and 250 µg dose levels of the vaccine was carried out (NCT04405076). Then, Phase 3 results of 95 participants after an interim analysis revealed 94.5% efficiency of the vaccine with no significant safety concerns [20].
The mRNA-1273 effectively produced neutralizing antibody titers in 8 participants of Phase 1 trial after receiving 25 µg or 100 µg doses. Neutralizing antibody titers of these participants were similar to the convalescent sera from COVID-19 recuperated patients [21]. Higher age adults subjects who received two doses of either 25 µg or 100 µg of the mRNA-1273 demonstrated safety and suffered mild or moderate effects including, fatigue, chills, headache, myalgia, and pain at the injection site [22]. In a preclinical study, mRNA-1273 prevented viral replication in the lungs and produced neutralized titers similar to subjects receiving 25 µg or 100 µg doses of the vaccine [23]. Another preclinical study consisting of nonhuman primates challenged with SARS-CoV-2 showed neutralizing activity and reduced inflammation and lung activity post administration of mRNA-1273 [24].
The mRNA-1273 also got the Fast Track designation from the US FDA. A Phase 3 trial of the vaccine is currently underway and is funded by the Operation Warp Speed [25]. One potential issue for this vaccine could be the storage temperature requirement of − 25° to − 15 °C is required [19].
AZD1222 by AstraZeneca and University of Oxford
On December 30, 2020, UK and on January 2, 2021, India approved AZD1222 COVID-19 vaccine developed by AstraZeneca and the Oxford Vaccine Group at the University of Oxford. It was previously called as ChAdOx1, a chimpanzee adenovirus vaccine [26, 27]. This group has previously developed a MERS vaccine. In India, this vaccine is jointly developed by Serum Institute of India and AstraZeneca and is branded as Covishield. A preclinical study showed significantly reduced viral load and humoral and cellular immune response [28]. Another preclinical study demonstrated an immune response in both mice and pigs [29]. ChAdOx1, a replication-deficient simian adenoviral vector expressing the full-length SARS-CoV-2 spike (S) protein, was commenced in April 2020 following preclinical studies involving non-human primates using a single dose. When one vs two doses of ChAdOx1 in both mice and pigs were compared, a single dose induced antigen-specific antibody and T cells responses, and a second booster dose enhanced antibody responses, particularly in pigs, with a significant increase in the level of SARS-CoV-2 neutralizing titers [29].
A Phase 1/2 (NCT04324606) study involving 1077 healthy adult participants aged 18–55 years, assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine, expressing the spike protein of SARS-CoV-2. The results demonstrated an acceptable safety profile for ChAdOx1 nCoV19 and increased antibody response by homologous boosting [30]. A Phase 3 trial (NCT04516746) is ongoing and has enrolled more than 40,000 subjects. Preliminary results have demonstrated that the safety profile of the vaccine candidate is acceptable, with most patients demonstrating an antibody response after one dose and all patients showing a response after two doses [30]. A Phase 3 trial in Brazil reported one death, which was confirmed by the Brazilian National Health Surveillance Agency (ANVISA). AstraZeneca stated that the results from the Phase 3 trial demonstrate immunogenicity, but have not yet publicly released any data [31]. An inhaled version of the vaccine candidate is also being tested in a small trial involving 30 participants [31].
The trials by AstraZeneca are funded by BARDA and Operation Warp Speed. IQVIA also announced they are partnering with AstraZeneca to advance clinical trials for this vaccine. Phase 3 trials are being conducted in the United States and India but were put on hold following reporting of a serious adverse event. Trials have since restarted. Additionally, EMAs human medicines committee (CHMP) and Health Canada have initiated a rolling review of AZD1222 to reduce the decision-making time related to safety and efficacy. The Australian Therapeutic Good Administration (TGA) granted AZD1222 provisional determination, the first step in the approval process. In Britain, the Medicines and Healthcare products Regulatory Agency (MHRA) has also started an accelerated review of AZD1222 [31]. This vaccine requires refrigeration (2–8 °C), which can potentially be problematic for use in low-income countries [19].
CoronaVac by Sinovac
CoronaVac (formerly PiCoVacc) is approved by China through EUA. CoronaVac is a formalin-inactivated and alum adjuvanted vaccine candidate developed by Sinovac Biotech, China [32]. Results from preclinical studies showed partial or complete protection in non-human primates exposed to SARS-CoV-2 [33].
A Phase 1/2 trial of 743 healthy participants (18–59 years old) who received two different dosages of the vaccine or placebo is active but not recruiting (NCT04551547). A Phase 1 trial of 143 participants (NCT04352608) and Phase 2 trial of 600 participants (NCT04383574) are both active but not recruiting. Phase 3 trial is underway (NCT04456595) to have 9000 participants. Trials are also ongoing in Turkey (NCT04582344) and in Indonesia (NCT04508075). Phase 1/2 trials revealed that the vaccine has good safety and immunogenicity with seroconversion occurring in 92.4% of participants after the 3 µg dose given on a 0–14 day schedule and 97.4% of participants with the same dose on a 0–28 day interval [34].
Preliminary results from the Instituto Butantan trial, declared by the Sinovac, showed CoronaVac is safe with no reported serious adverse events. However, the trial in Brazil was briefly suspended due to patient death, though the trial has resumed later [35].
COVID-19 vaccine by Sinopharm and the Wuhan Institute of Virology, China
China approved this vaccine via EUA. Sinopharm and Wuhan Institute of Virology under the Chinese Academy of Sciences have developed an inactivated CVC [36]. A Phase 1/2 clinical trial (ChiCTR2000031809) involving healthy subjects is ongoing. According to a release from China National Biotec Group, this vaccine has demonstrated a strong neutralizing antibody response. Phase 1 and Phase 2 trials data also showed immunogenicity [37]. A Phase 3 trial is in progress in Peru, Morocco, and United Arab Emirates.
Sputnik V by the Gamaleya Research Institute, Russia
Russia has approved first CVC as Sputnik V (previously as Gam-COVID-Vac). The Gamaleya Research Institute in Russia and Health Ministry of the Russian Federation are assessing their non-replicating viral vector vaccine, Sputnik V, in a Phase 3 trial. However, there is no trial data available to date. This led to criticism as even there is a lack of data on safety and efficacy, the vaccine is approved.
Two Phase 1/2 trials with 38 subjects each were conducted (NCT04436471, NCT04437875). Sputnik V is additionally being evaluated in a small Phase 2 trial with 110 subjects older than 60 years (NCT04587219). A Phase 3 trial with about 40,000 participants is also in progress (NCT04530396). Aside from Russia, Sputnik V is also being evaluated in Belarus (NCT04564716) and the United Arab Emirates. The results from the Phase 1/2 trials demonstrated the safety and immunogenicity of the vaccine [38]. The Russian Direct Investment Fund also announced that Sputnik V is 92% effective based on the interim trial results from 20 participants. A preliminary pre-submission of the vaccine has also been proposed in Brazil [39].
BBIBP-CorV by Sinopharm and Beijing Institute of Biological Products, China
BBIBP-CorV is inactivated CVC developed by Sinopharm in association with Beijing Institute of Biological Products, China. Firstly China and later on United Arab Emirates (UAE) approved the vaccine through EUA [36].
BBIBP-CorV is currently being assessed in Phase 2 (CHiCTR2000032459) and Phase 3 trial in China (ChiCTR2000034780) as well as Phase 3 trial in Argentina (NCT04560881). BBIBP-CorV is shown to be highly effective in preventing disease against SARS-CoV-2 in Rhesus macaques [40]. Phase 1 results showed that BBIBP-CorV was safe and tolerated at all dose levels, with all participants showing a humoral response to the vaccine after 42 days. The UAE announced that the vaccine is 86% effective [41].
EpiVacCorona by Federal Budgetary Research Institution State Research Center of Virology and Biotechnology, Russia
Russia also granted regulatory approval to EpiVacCorona, a peptide vaccine candidate for COVID-19, developed by Federal Budgetary Research Institution State Research Center of Virology and Biotechnology [42].
A Phase 1/2 trial in Russia is assessing the effectiveness of the vaccine (NCT04527575). A Phase II clinical trial of the vaccine was completed recently. Head of the zoonotic diseases and flu department with the State Research Center of Virology and Biotechnology has said “participants have developed immunity a month after the first vaccination” [43], but there is no data available in the public domain.
Covaxin by Bharat Biotech and National Institute of Virology, India
On January 2, 2021, India approved an inactivated vaccine called Covaxin, developed by Bharat Biotech and India’s National Institute of Virology [27]. A Phase 1/2 trial of about 1100 healthy subjects is ongoing after obtaining permission from the Drug Controller General of India. The Indian Council of Medical Research (ICMR) reported that Covaxin has entered Phase 2 clinical trials. On October 27, 2020, the ICMR approved Covaxin for Phase 3 trial. Results of a two-dose regimen study administered to Rhesus macaques demonstrated an increase in SARS-CoV-2 specific IgG and neutralizing antibodies as well as diminished viral replication in the nasal cavity, throat, and lungs [44]. According to the trial principal investigator, initial results from the first fifty participants who received the vaccine seem to be promising. In addition, according to Bharat Biotech, the first two phases of the trial did not demonstrate any major adverse events [45]. The proposed distribution for this vaccine is February 2021, according to an ICMR scientist who spoke with Reuters.