key: cord-1009377-rxk8l5n4
authors: Alhinai, Zaid A; Elsidig, Nagi
title: Countries with similar Covid-19 vaccination rates yet divergent outcomes: are all vaccines created equal?
date: 2021-06-23
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.06.040
sha: 5c06e8eebff7e47005d97b1aacf6039c4fc911eb
doc_id: 1009377
cord_uid: rxk8l5n4

The world is currently engaged in a race of vaccination vs. infection in an effort to control the Covid-19 pandemic. Some countries have already achieved high vaccination rates, offering a glimpse into the so-called “post-vaccination” world. We describe here a striking comparison between the similarly-sized and neighboring countries of Bahrain and Qatar. While both countries have achieved impressive vaccination rates, cases increased to unprecedented levels in one country, while decreasing steadily in the other. Although this could be attributed to a number of factors, we argue here that the heavy reliance on alum-adjuvanted inactivated virus vaccines may have contributed to these discrepant outcomes. We then expand the analysis to compare the top 10 vaccinated countries, and compare their outcomes based on their reliance on inactivated virus vaccines. The results remarkably align with the initial findings seen in Bahrain and Qatar. Countries that did not use inactivated virus vaccines achieved steady declines in daily Covid-19 deaths, while other countries did not. This work highlights the urgent need to further study the effectiveness of alum-adjuvanted inactivated virus vaccines for Covid-19 before expanding their use.

The world is currently engaged in a race of vaccination vs. infection in an effort to control the Covid-19 pandemic. Some countries have already achieved high vaccination rates, offering a glimpse into the so-called "post-vaccination" world. We describe here a striking comparison between the similarly-sized and neighboring countries of Bahrain and Qatar. While both countries have achieved impressive vaccination rates, cases increased to unprecedented levels in one country, while decreasing steadily in the other. Although this could be attributed to a number of factors, we argue here that the heavy reliance on alum-adjuvanted inactivated virus vaccines may have contributed to these discrepant outcomes. We then expand the analysis to compare the top 10 vaccinated countries, and compare their outcomes based on their reliance on inactivated virus vaccines. The results remarkably align with the initial findings seen in With the race to vaccinate the world against SARS-CoV-2 well on its way, many countries have already achieved impressive vaccination rates, and are quickly reaping the benefits. Yet not all highly-vaccinated populations are seeing the same results. A striking example of such divergent outcomes is currently being seen in the neighboring states of Qatar and Bahrain. In an impressive feat, both nations have vaccinated more than 50% of their population. And while in Qatar infection rates have decreased in a reassuring manner, infection rates have surprisingly sky-rocketed to unprecedented and alarming levels in Bahrain ( Figure 1 ).

What could possibly explain such divergent outcomes? While multiple factors are likely at play here, there is a major difference between the two countries in the types of vaccines being deployed. In Bahrain, the most commonly used vaccine has been the BIBP (Sinopharm) vaccine, accounting for approximately 60% of its inoculations (Trofimov and Said, 2021) . Qatar, on the other hand, has relied solely the BNT162b2 (Pfizer/BioNTech) and mRNA-1273 (Moderna) vaccines(Qatar COVID19 Vaccine COVID-19 Vaccine, n.d.).

There is a significant difference in the immune responses elicited by the different vaccines. The BIBP vaccine's mechanism is based on an inactivated SARS-CoV-2 virus with an alum adjuvant. It has been shown to efficiently induce the production of neutralizing antibodies , but there are no studies that directly compare the neutralizing antibody activity from this vaccine to others. One study by Khoury et al used modeling to predict the protective efficacy of different vaccines in preventing symptomatic SARS-CoV-2 infection based on neutralizing antibody titers (Khoury et al., 2021) . While this study did not address the BIBP vaccine directly, it did show that Coronavac, which is also an alumadjuvanted inactivated virus vaccine, had less protective efficacy compared to mRNA and adenovirus-vector vaccines, and that lower protective efficacy correlated strongly with lower 4 neutralizing antibody titers. This study also predicted that a lower starting efficacy would result in a larger reduction in efficacy over time and against variants (Khoury et al., 2021) .

Another difference between the BIBP vaccine on the one hand, and mRNA and adenovirus-vector vaccines on the other, is cellular immune responses. Data on the cellular immune responses to the BIBP vaccine is lacking. However, it is generally accepted that alum-adjuvanted inactivated virus vaccines induce no or weak cellular responses, specifically cytotoxic CD8 T cell responses (Jeyanathan et al., 2020) . On the other hand, mRNA and adenovirus-vector vaccines have shown robust, Th1 predominant cellular adaptive immune responses, with the production of antigen-specific CD4 and CD8 T cells (Anderson et al., 2020; Ewer et al., 2021; Jeyanathan et al., 2020; Walsh et al., 2020) (Anderson et al., 2020; Ewer et al., 2021; Walsh et al., 2020) . The presence of cellular immune responses in combination with neutralizing antibodies is thought to confer long-lasting immunity, and improve outcomes in the case of acute infection (Dan et al., 2021; Rydyznski Moderbacher et al., 2020) . In addition, while emerging SARS-CoV-2 variants of concern have shown significant escape from neutralizing antibody activity, the activity of cellular immune responses against variants appears to be preserved (Geers et al., 2021) .

As such, a potential hypothesis to explain the divergent epidemiologic outcomes observed between Qatar and Bahrain is that the BIBP vaccine used heavily in Bahrain induces weaker humoral responses, cellular responses, or both. While it is true that the BIBP vaccine showed an efficacy of 73-78% against symptomatic infection, according to an interim-analysis of a phase 3 RCT of the vaccine(Al Kaabi et al., 2021) , it should be noted that the data was collected on young healthy adults (mean age 36.1 years), and for a median follow-up of only 77 days, ending on December 20, 2020. As such, we do not have conclusive data on the duration of protection conferred by the BIBP vaccine, its efficacy in vulnerable populations, its efficacy against variants of concern, its efficacy in preventing severe disease, or its efficacy in preventing transmission of infection. On the other hand, efficacy in the above domains has been demonstrated for mRNA as well as adenovirus-vector vaccines(Public Health England, 2021).

Although the divergent outcomes observed in Qatar and Bahrain are potentially the most striking, the trend seems to hold true in other countries as well. Looking at countries with a population exceeding 500,000 and with vaccination data updated as of June 2, 2021, among the ten countries with the highest doses of Covid-19 vaccines administered per capita, five relied in part on alum-adjuvanted inactivated virus vaccines: Bahrain, Chile, Hungary, Maldives, and Mongolia (Hannah et al., 2021; Snyder and Root-Wiley, 2021) . The other five countries among the top ten -Israel, Malta, Qatar, United Kingdom and United Statesrelied only on mRNA and/or adenovirus-vector vaccines (Hannah et al., 2021; Snyder and Root-Wiley, 2021) . Figure 2 shows data from these ten countries. While the 10 countries have achieved high vaccination rates, on June 4, 2021, all 5 countries that relied on inactivated virus vaccines had higher daily Covid-19 deaths per million people (Figure 2, A and B) .

Additionally, the trend for the average daily Covid-19 deaths per million population across the 5 nations that did not rely on inactivated virus vaccines showed a steady decline after January 31, 2021. However, for the other 5 nations, which relied on inactivated virus vaccines, such a decline was not observed (Figure 2 , C and D). Thus, across highlyvaccinated countries, the reliance on inactivated virus vaccines seems to be associated with worse outcomes.

An alternative explanation for such discrepancies in outcomes is that countries with high or increasing mortality rates simply relaxed social distancing measures too quickly.

However, what is the likelihood that all 5 countries that relied on inactivated virus vaccines made that same error? There is also a significant difference in the socioeconomic status of the countries being compared. The combined GDP per capita of the 5 countries that relied on 6 inactivated virus vaccines was $14,069, compared to $56,187 for the other countries (Nominal, 2017) . This is a factor that may contribute to a country's ability to control the spread of infection. However, it should be noted that the 5 countries with lower GDP per capita had, on average, better control of the pandemic at the start of their vaccination campaigns compared to the 5 other countries (Figure 2, C and D) . Additionally, if there was no drop in effectiveness of the vaccines, then why are some countries now offering an extra dose of an mRNA vaccine to those who already received two doses of an inactivated virus vaccine (Trofimov and Said, 2021) ?

To be sure, the evidence presented in this short communication is circumstantial, and not conclusive. To arrive at more conclusive answers, scientific studies on the long-term efficacy of alum-adjuvanted inactivated virus vaccines, their efficacy in vulnerable populations, their efficacy in preventing severe disease, their efficacy in preventing transmission of infection, and their efficacy against variants of concern are urgently needed. Such evidence should be considered before more resources are allocated towards the deployment of these vaccines.

The danger of deploying vaccines that may not provide sufficient long-lasting protection or protection against variants of concern is that new waves of infection may return and more variants of concern may emerge. Additionally, the deployment of sub-optimal vaccines may threaten trust in vaccination campaigns on the whole. Conflict of interest: The authors certify that they have no affiliations with or involvement in any organization or entity with any financial or non-financial interest in the subject matter or materials discussed in this article.

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

No funding was provided for this research.

This research, relying exclusively on publicly available information, did not require ethical review. The numbers reflect a rolling 7-day average on each date. Countries were included if their

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