Steady stream of Phase III COVID-19 vaccine data to flow into the new year
The dizzying pace of COVID-19 vaccine readouts over the last three weeks is only going to accelerate over the next five.
By the end of the year, three of the four leading vaccines are likely to yield their next interim or their final readout, and four more programs are expected to report initial Phase III results.
The latter category includes the first two inactivated virus vaccines against SARS-CoV-2, Coronavac from Sinovac Biotech Ltd. (NASDAQ:SVA) and Vero Cell from China National Biotech Group (Sinopharm). The modality could offer a broader immune response to more SARS-CoV-2 antigens than spike-targeted vaccines, which represent the bulk of the pipeline.
The other two new vaccines likely to yield first Phase III data at or before year-end will shed more light on viral vector vaccines. While strong efficacy reported this month for mRNA-1273 from Moderna Inc. (NASDAQ:MRNA) and BNT162b2 from Pfizer Inc. (NYSE:PFE) and BioNTech SE (NASDAQ:BNTX) validated mRNA as a vaccine modality, the efficacy findings for viral vector vaccines have been more complicated to interpret.
Additional readouts from viral vector vaccines will help determine the best dosing schedules for avoiding efficacy-killing anti-vector immune responses.
Looking ahead to the first quarter of 2021, as many as 10 more late-stage readouts could come from COVID-19 vaccines, including three additional modalities: protein-based vaccines, a DNA vaccine and a peptide vaccine.
Phase III readouts from JNJ-78436735 from Johnson & Johnson (NYSE:JNJ) and Ad5-nCoV from CanSino Biologics Inc. (HKEX:6185; Shanghai:688185) will add two more data points to help understand the best use of adenovirus vectors in vaccine delivery, and the problem of immune responses targeted at the vectors.
On Tuesday, Sputnik V from Russia’s Gamaleya National Center of Epidemiology and Microbiology produced a 91.4% protection rate at an interim analysis, a number on par with Moderna’s 94.5% and Pfizer-BioNTech’s 95% protection rates, albeit from fewer case numbers. Sputnik V’s interim analysis was based on 39 confirmed cases of COVID-19, whereas Moderna’s interim analysis was based on 95 cases and Pfizer-BioNTech’s final analysis on 170 cases.
Sputnik V’s next interim readout, which is expected in December, will come at 78 cases, still shy of the other two vaccines. Final analysis of the vaccine is expected in May 2021.
AstraZeneca plc (LSE:AZN; NASDAQ:AZN) and partner University of Oxford reported preliminary Phase III data from viral vector vaccine AZD1222 on Nov. 23 showing that a partial dose of the vaccine followed by a full-dose boost performed better than two full doses, with protection rates of 90% and 62%, respectively.
The results came from combining initial data from two separate trials with differences in their protocols, and more data are needed to flesh out the result.
The stronger efficacy of the lower dose was unexpected, and one hypothesis contends that subjects who initially received the full dose mounted a stronger immune response against the vaccine’s viral vector than those who initially received a partial dose, which then dampened their response to the second dose.
University of Oxford, which developed AZD1222, chose a chimpanzee adenovirus vector for the vaccine, in part, because it avoids the pre-existing anti-vector immunity that can occur with human adenovirus vectors in trial participants who have previously been exposed to the adenovirus. But lack of pre-existing immunity does not preclude induction of immunity upon vaccination.
Sputnik V uses two human adenovirus vectors, which means it could be susceptible to pre-existing anti-vector immunity, but the vaccine circumvents the problem of vaccination-induced anti-vector immunity by using one vector for the initial dose and another for the second dose.
J&J’s upcoming Phase III readout will test the efficacy of a single dose of JNJ-78436735, which uses one of the two vectors in Sputnik V, human serotype 26 adenovirus (Ad26). In addition, the pharma started a second Phase III trial last week testing two vaccine doses, both of which use the Ad26 vector. J&J did not respond to an inquiry about whether the first dose of the vaccine will be lower than the second dose — the regimen that seemed to work better for AZ.
According to ClinicalTrials.gov, CanSino has a primary completion date on Nov. 30 from a small, Russian Phase III study testing the immunogenicity of its viral vector vaccine Ad5-nCoV, which uses an adenovirus type 5, the other vector type used in Sputnik V. The trial’s primary endpoint is a four-fold increase in anti-receptor-binding domain antibodies, and its exploratory endpoints include T cell responses and rates of confirmed infections.
On Nov. 7, CanSino announced the launch of Phase III testing in Mexico. According to the ClinicalTrials.gov record, the Mexican sites are part of a global Phase III trial that started recruiting in September. The trial is testing a single dose of Ad5-nCoV.
Ad5-nCoV has produced lower neutralizing antibody titers in early-stage trials than its competitors, though each company uses a different assay to measure titers, precluding direct comparisons. In addition, both a Phase I study published in The Lancet in May and a Phase II study in The Lancet in July found that about half of subjects had pre-existing antibodies against the vaccine’s Ad5 vector that muted neutralizing antibody responses and T cell responses to vaccination.
In the second paper, the authors wrote, “Pre-existing anti-Ad5 immunity is considered to be the biggest obstacle for the candidate Ad5-vectored COVID-19 vaccine to overcome. A flexible additional dose (between months 3 and 6) might be a potential solution.”
Looking to 2021
While the leading mRNA and viral vector COVID-19 vaccines are based on new or relatively new technologies, more conventional vaccine formats are not far behind.
In addition to the inactivated virus vaccines from Sinopharm and Sinovac that could yield data this year, Bharat Biotech International Ltd. and the Indian Council of Medical Research (ICMR) started a Phase III trial of an inactivated virus vaccine on Monday. Depending on the speed of recruitment and the rates of infection over the next few months, Bharat’s trial could read out by 2Q21.
Novavax Inc. (NASDAQ:NVAX) will likely be first to report Phase III data from a protein-based vaccine for COVID-19. A U.K. trial of NVX-CoV2373 is expected to read out in early 2021 and a U.S. trial is slated to start this month. Like the other two protein-based vaccines, it delivers antigen from the spike protein.
Chongqing Zhifei Biological Products Co. Ltd. (SZSE:300122) started a Chinese Phase III trial of its protein vaccine on Nov. 18 and plans to start Phase III testing in Uzbekistan by the end of November, followed by testing in Indonesia, Pakistan and Ecuador.
Sanofi (Euronext:SAN; NASDAQ:SNY) hopes to start a Phase III trial of its SARS-CoV-2 vaccine in December, assuming all goes well with its ongoing Phase I/II study. According to the pharma’s website, it plans to request regulatory approval in the first half of next year. Sanofi is pairing the vaccine with an adjuvant from GlaxoSmithKline plc (LSE:GSK; NYSE:GSK).
1Q21 could see data from another mRNA vaccine, CVnCoV from CureVac N.V. (NASDAQ:CVAC), which plans to start a Phase II/III study by December, as well as from DNA vaccine INO-4800 from Inovio Pharmaceuticals Inc. (NASDAQ:INO) and peptide vaccine UB-612 from Vaxxinity, formerly the COVAXX unit of United Biomedical Inc., which are both slated to enter late-stage testing by year-end.
With EUAs expected soon for the two leading COVID-19 vaccines, the window for testing additional vaccine candidates in the U.S. could start to close.
Given the gravity of the pandemic, some stakeholders believe it would be ethical to unblind ongoing trials after authorization to give subjects the opportunity to switch a vaccine deemed effective. Even if unblinding doesn’t occur, as authorized vaccines start to become widely available, it could become harder to convince patients to enroll in clinical trials.