This trial reports a vaccine efficacy of 44%, based on 247 vs 119 infections in the vaccine and placebo arms, respectively. However, the study excludes infections occurring before 14 days after the second dose. The entire study relies on a per-protocol analysis, which introduces a significant issue.
If we consider the number of COVID-19 cases between the first injection and 14 days after the second dose, the data shows 369 infections in the SpikoGen arm versus 48 in the placebo arm. Given the randomized nature of the trial, this discrepancy is concerning and suggests a potential vaccine-induced increase in early infections. A chi-square test reveals a statistically significant (p < 0.001) 161% increase in the risk of PCR-confirmed infection immediately following vaccination.
Although I do not claim any misconduct, this oversight significantly affects the interpretation of the results. Had the authors conducted an intention-to-treat (ITT) analysis—including all patients from the first dose onwards who developed a PCR-confirmed infection—there would have been 616/12,410 cases in the vaccine group versus 167/4,219 in the placebo group. This suggests that the vaccine efficacy could be close to 0% if analyzed from the first dose, as infections occurred at similar rates in both groups.
Furthermore, this trial was conducted as part of a commercial collaboration between Vaxine (Australia) and CinnaGen (Iran), with SpikoGen being manufactured in Iran. SpikoGen has not been tested for efficacy in Australia. Vaxine’s CEO, Nikolai Petrovsky, faced criticism in Australia for not publishing efficacy data on SpikoGen, and this paper appears to serve as a response to those concerns (PIIS1198743X22004645).
In comparison to other vaccines, such as Novavax (reported 90% efficacy in NEJM 2021;385:1172), SpikoGen's reported efficacy of 44% against symptomatic infection and 78% against severe disease appears lower, as evident from the Kaplan-Meier incidence curves.
There are also flaws in the trial design. The inclusion of participants with a prior history of COVID-19 could have introduced bias, as pre-existing immunity might have influenced the outcomes. Moreover, the ITT analysis should have been included, as this is standard practice in clinical trials. When recalculating the infection rates in an ITT analysis, the rates are 4.9% (vaccine) vs. 4.0% (placebo), which is likely not statistically significant.
While I doubt that a protein subunit vaccine like SpikoGen would have caused or contributed to infection, this trial's statistical handling and exclusion of early cases raise significant questions about the validity of the reported efficacy.
Finally, the immunogenicity and safety of SpikoGen as a booster vaccine are described in another paper (Tabarsi et al., Immunology 2022;167:340–353). However, this study, while demonstrating increased antibody titers, lacks any evidence of clinical efficacy in boosted patients.
Overall, these issues, especially the lack of an ITT analysis, need to be addressed, and a correction or clarification from the authors would be appreciated to ensure transparency in the reporting of vaccine efficacy.
Dear Sirs, Thank you for your interest in the paper entitled” “Evaluating the Efficacy and Safety of SpikoGen®, an Advax-CpG55.2-adjuvanted SARS-CoV-2 Spike Protein Vaccine: A Phase 3 Randomized Placebo-Controlled Trial”. Here are the explanations regarding your comments:
The predefined protocol approved by the regulator, specified that populations would be analyzed as follows: Safety Analysis Dataset will include participants who took at least one dose of the study intervention. The analysis will be based on the study intervention that subjects actually receive. Sensitivity Analysis Dataset 1 (SEN1) will include participants who took both doses of the study intervention within the specified time window and were not discontinued/withdrawn from the study until 14 days after the second dose (day 35). The analysis will be based on the randomized intervention assignment. Sensitivity Analysis Dataset 2 (SEN2) will include a subset of the participants in the SEN1 Analysis Dataset who had no major protocol deviations that may affect the study data. The protocol deviations will be assessed for their impact prior to database lock and unblinding of the study data, and may include participant discontinuation/withdrawal and administration of another COVID-19 vaccine during the study period. The analysis will be based on the randomized intervention assignment.
Per-Protocol Analysis Dataset (PP) will include a subset of the participants in the SEN2 Analysis Dataset who were negative for anti-nucleocapsid IgG antibodies at baseline. The analysis will be based on the randomized intervention assignment. As defined, the whole conclusion was not based on per-protocol analysis We included all deviations in another sensitivity analysis dataset. However, as SpikoGen is a 2-dose vaccine, all the analyses were done since, 14 days after second dose, including those with and without protocol deviations. Therefore, the presence of PCR positive cases at this time does not necessarily indicate that the vaccine is ineffective, as these cases occurred prior to receiving the second dose. SpikoGen is a 2-dose vaccine and we did not have any claims regarding the first dose efficacy. That’s why we did not aim to analyze participants with first dose in the predefined protocol. The main point is that all these decisions were predefined in the approved protocol. One potential explanation for the increased number of PCR positive cases prior to the second dose in the SpikoGen group is that participants who experienced greater pain at the injection site may have believed they had received the vaccine. Consequently, believing they were protected, these individuals may have engaged in more public activities and risky behaviors. Given that the vaccine had not yet reached its full effectiveness, these individuals were more susceptible to infection and development of COVID-19.
Another main point is that there are no methodological issues with recruitment of participants with potential previous history of SARS-CoV-2. In the predefined protocol, participants with and without seropositivity for nucleocapsid were analyzed as two sensitivity analysis datasets. Moreover, there is no known proven method which guarantee the prior history of COVID-19. Many participants may have asymptomatic infection before. Moreover, in Table 1, the participants with N positive serology are balanced between the two groups. In the Novavax paper also only known histories of SARS-CoV-2 infections are excluded. Regarding the comment concerning the efficacy of SpikoGen compared to previous vaccines including Novavax, as highlighted in the paper, it is not possible and appropriate to directly compare our efficacy results with other vaccine trials, given differences in populations, endpoints, and timing. Furthermore, our vaccine efficacy was measured in response to a major wave of delta variant in Iran which contrasts with Phase 3 trials for earlier approved vaccines where the interim analyses leading to approval were conducted prior to the delta variant. In the Novavax paper published in NEJM, it is written that: “Because case accrual for this analysis occurred during the first half of 2021, when the delta variant of concern had not been widely established throughout the United States or Mexico, no Covid-19 efficacy end-point cases due to this variant were accrued, and thus the vaccine efficacy against delta and other newer variants could not be established.” Overall, COVID-19 vaccine effectiveness against delta has been found to be reduced when compared to more ancestral strains with, for example, a test negative case control study showing 2 dose effectiveness of the AstraZeneca ChAdOx1 to be only 59.8% (95%CI; 28.9 - 77.3) against B.1.617.2 (delta) versus 66.1% (95% CI; 54.0 - 75.0) for the earlier B.1.1.7 (alpha) variant. The same study showed the effectiveness of two doses of BNT162b2 mRNA vaccine dropped from 93.7% against alpha to 88.0% against delta. Similarly, a US Department of Veterans Affairs study showed the effectiveness in September 2021 of 2 doses of vaccine against delta was just 13.1%, for the Janssen adenoviral vector vaccine, 43.3% for Pfizer mRNA vaccine and 58% for Moderna mRNA vaccine, having been earlier measured in March 2021 against the earlier strains (predominantly alpha) as 86.4%, 86.9% and 89.2%, respectively. All these papers are cited in our paper.
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