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content/22.vaccines-trad.md

@@ -72,7 +72,7 @@ Beyond the variability introduced by time and geography, efficacy within a trial
 Patients participating in a clinical trial are likely to receive more medical oversight, resulting in better follow-up, adherence, and patient engagement [@pubmed:17112328].
 Additionally, the criteria for participant inclusion in a trial often bias trials towards selection of younger, healthier individuals [@doi:10.1093/rheumatology/key109].
 The ability of an RCT to accurately assess safety can be biased by the fact that a clinical trial might not reveal rare adverse events (AEs) that might become apparent on a larger scale [@doi:10.1093/rheumatology/key109].
-Therefore, while clinical trials are the gold standard for evaluating vaccines for COVID-19, the results of these trials must be considered in a broader context when real-world data is available. 
+Therefore, while clinical trials are the gold standard for evaluating vaccines for COVID-19, the results of these trials must be considered in a broader context when real-world data is available.
 
 While the relationship between a vaccine and a pathogen is not static, the data clearly demonstrates that a variety of efficacious vaccines have been developed against SARS-CoV-2.
 Here we discuss a selection of programs that use well-established vaccine biotechnologies.
@@ -212,7 +212,7 @@ Table: Inactivated whole-virus vaccines approved in at least one country [@url:h
 
 Several whole-virus vaccines have been developed against COVID-19 and are available in countries around the world (Table @tbl:approved-whole-virus).
 As of {{owid_most_recent_date}}, {{owid_inactivated_count}} vaccines developed with IWV technology are being distributed in {{owid_inactivated_countries}} countries (Figure @fig:iwv-distrib).
-Evidence about the value of these vaccines to combat SARS-CoV-2 is available not only from clinical trials, but also from their roll-out following approval. 
+Evidence about the value of these vaccines to combat SARS-CoV-2 is available not only from clinical trials, but also from their roll-out following approval.
 Here, a major consideration has been that vaccines often lose efficacy as mutations accumulate in the epitopes of the circulating virus; IWV vaccines may be particularly affected in such cases [@doi:10.3389/fimmu.2019.00594].
 This loss of specificity over time is likely to be influenced by the evolution of the virus, and specifically by the rate of evolution in the region of the genome that codes for the antigenic spike protein.
 Here we review three vaccine development programs and their successes in a real-world setting.
@@ -241,14 +241,14 @@ As of December 2022, a total of 17 CoronaVac trials had been registered in a var
 Two of the earliest phase III trials to produce results examined a two-dose regimen of CoronaVac following a 14-day prime boost regimen [@doi:10.1093/cid/ciab823; @doi:10/gk898z].
 These trials were conducted in Turkey [@doi:10/gk898z] and Chile [@doi:10.1093/cid/ciab823] and enrolled participants over an identical period from September 2020 and January 2021.
 The Chilean trial, which reported interim results regarding safety and immunogenicity, identified specific IgG nAbs against the S1 RBD and a robust IFN-γ secreting T cell response was induced via immunization with CoronaVac [@doi:10.1093/cid/ciab823].
-In the Turkish trial, VE was estimated to be 83.5% against symptomatic COVID-19 [@doi:10/gk898z]. 
+In the Turkish trial, VE was estimated to be 83.5% against symptomatic COVID-19 [@doi:10/gk898z].
 In the safety and immunogenicity study, minimal AEs were reported [@doi:10/gk898z], and 18.9% of participants in the vaccine arm of the Turkish trial reported AEs compared to 16.9% of participants in the placebo group [@doi:10/gk898z].
 However, 2% (n=7) of Turkish participants aged 18 to 59 reported severe AEs [@doi:10/fx8z], causing the trial to be halted for investigation [@url:https://www.nytimes.com/interactive/2020/health/sinovac-covid-19-vaccine.html].
 The investigation determined that these events were unrelated to the vaccine [@doi:10/fx8z; @url:https://www.nytimes.com/interactive/2020/health/sinovac-covid-19-vaccine.html].
 
 An additional phase III trial was conducted in Brazil between July and December 2020 following a randomized, multicenter, endpoint driven, double-blind, placebo-controlled design and enrolling nearly 10,000 healthcare workers [@doi:10.1186/s13063-020-04775-4; @doi:10.2139/ssrn.3822780].
 The preprint reporting the results of this study [@doi:10.2139/ssrn.3822780] reports an efficacy of 50.7% against symptomatic COVID-19 and 100% against moderate to severe cases.
-A large percentage of participants, 77.1% in the vaccine group and 66.4% in the placebo group, reported AEs, including two deaths, but all of the serious AEs were determined not to be related to the vaccine [@doi:10.2139/ssrn.3822780]. 
+A large percentage of participants, 77.1% in the vaccine group and 66.4% in the placebo group, reported AEs, including two deaths, but all of the serious AEs were determined not to be related to the vaccine [@doi:10.2139/ssrn.3822780].
 CoronaVac also appears to be suitable for use in immunocompromised patients such as those with autoimmune rheumatic diseases according to phase IV trials [@doi:10.1038/s41591-021-01469-5], and the vaccine was also well tolerated and induced humoral responses in phase I trials in children aged 3 to 17 years, which will now be examined in phase II and III clinical trials [@doi:10/gn93].
 
 Estimates of CoronaVac's VE have varied across trials.
@@ -331,7 +331,7 @@ Therefore, the data suggest that the vaccine does continue to confer protection
 
 The authorization of Covaxin has also offered opportunities to monitor how well the clinical trial results translate into a real-world setting.
 Additionally, an effort to monitor AEs and COVID-19 cases following vaccine roll-out reported that most side effects were mild and that cases were rare, even though this data would seem to have been collected during the severe wave of COVID-19 brought on by the Delta VOC in India in early 2021; at the same time, the sample sizes were extremely small [@doi:10.53411/jpadr.2021.2.3.5].
-Similarly, larger studies of adults (June to September 2021) [@doi:10.1002/jmv.27655] and adolescents (beginning in January 2022) [@doi:10.1007/s40264-022-01226-8] who received the vaccine outside of a trial setting reported that safety was similar across age groups, with no severe AEs reported in adults and with no serious AEs reported in adolescents, although 0.9% (6 individuals) reported severe AEs. 
+Similarly, larger studies of adults (June to September 2021) [@doi:10.1002/jmv.27655] and adolescents (beginning in January 2022) [@doi:10.1007/s40264-022-01226-8] who received the vaccine outside of a trial setting reported that safety was similar across age groups, with no severe AEs reported in adults and with no serious AEs reported in adolescents, although 0.9% (6 individuals) reported severe AEs.
 However, a much lower effectiveness (22-29%) was estimated in a real-world setting during an analysis of cases in healthcare workers from April to May 2021 [@doi:10.1080/21645515.2022.2034456].
 All the same, monitoring of hospitalized COVID-19 patients between April and June 2021 indicated that the vaccines were highly effective against preventing severe illness [@doi:10.1101/2021.08.26.21262705].
 
@@ -354,7 +354,7 @@ Additionally, safety audits have proactively identified concerns, as demonstrate
 More concern has arisen around the issue of effectiveness due to the reduced neutralizing activity of IWV vaccines against VOC relative to the index strain.
 In several cases, estimates of VE have varied widely across different trials of a single vaccine.
 Such issues are likely to be exacerbated by spatiotemporal differences in viral evolution, though in the case of the very high estimate generated by the Turkish trial of CoronaVac [@doi:10/gk898z], the design of the study may have inflated the VE estimate [@doi:10/jrrf].
-Regardless, the authors of the original trial argued that all of the trials suggest a very high efficacy against severe disease [@doi:10/jrrg], as is the case for all of the IWV vaccines discussed here. 
+Regardless, the authors of the original trial argued that all of the trials suggest a very high efficacy against severe disease [@doi:10/jrrg], as is the case for all of the IWV vaccines discussed here.
 In addition to issues related to the evolution of SARS-CoV-2, it is important to consider the duration of immunity over time.
 With IWV vaccines, heterologous vaccine boosters are being considered in many cases.
 Today, the WHO has developed recommendations for booster immunization for several whole-virus vaccines.
@@ -480,7 +480,7 @@ Boosters may be especially important given that Omicron and related variants, in
 Given the apparent need for boosters, interest has also emerged in whether booster doses of Nuvaxovid can be safely administered along with annual flu vaccines.
 In a subgroup of approximately 400 patients enrolled from the U.K. phase III trial who received either Nuvaxovid or a placebo at a ratio of 1:1, a concomitant dose of adjuvanted seasonal influenza vaccines (either a trivalent vaccine or a quadrivalent vaccine) was administered [@doi:10.1101/2021.06.09.21258556].
 This study demonstrated that the vaccines could be safely administered together [@doi:10.1101/2021.06.09.21258556].
-While no change to the immune response was noted for the influenza vaccine, a notable reduction of the antibody response elicited by Nuvaxovid  was reported, but efficacy was still high at 87.5% [@doi:10.1101/2021.06.09.21258556].
+While no change to the immune response was noted for the influenza vaccine, a notable reduction of the antibody response elicited by Nuvaxovid was reported, but efficacy was still high at 87.5% [@doi:10.1101/2021.06.09.21258556].
 Novavax has since started phase I/II trials to investigate the administration of its own influenza vaccine, NanoFlu, concomitantly with Nuvaxovid [@url:https://ir.novavax.com/2021-09-08-Novavax-Initiates-Phase-1-2-Clinical-Trial-of-Combination-Vaccine-for-COVID-19-and-Seasonal-Influenza].
 The combination appeared to be safe and effective in preclinical studies [@doi:10.1101/2021.05.05.442782].
 
@@ -608,7 +608,7 @@ Therefore, vaccine development programs that utilized established vaccine techno
 The total number of doses of the original formulation of each vaccine that were distributed within each country as of {{owid_most_recent_date}}, by platform type, is shown as a function of GDP.
 These data are retrieved from Our World in Data [@url:https://ourworldindata.org/coronavirus; @doi:10.1038/s41562-021-01122-8] and plotted using the Python package plotnine [@url:https://github.com/has2k1/plotnine].
 Lines show a general trend in the data and are drawn using geom_smooth [@url:https://ggplot2.tidyverse.org/reference/geom_smooth.html].
-The list of countries included in the dataset is available from OWID [@url:https://github.com/owid/covid-19-data/blob/master/public/data/vaccinations/locations.csv]. 
+The list of countries included in the dataset is available from OWID [@url:https://github.com/owid/covid-19-data/blob/master/public/data/vaccinations/locations.csv].
 See https://greenelab.github.io/covid19-review/ for the most recent version of this figure, which is updated daily.
 Axes are not scaled per capita because both variables are modulated by population size.
 ]({{owid_doses_scatterplot}} "Distribution of vaccines according to GDP"){#fig:gdpscatter secno=1}
@@ -640,21 +640,21 @@ The initiative by Texas Children’s Hospital and Baylor College of Medicine to
 Corbevax can be produced at low cost using existing technology and is now licensed to Biological E. Limited (BioE), an Indian company specializing in low-cost vaccine production [@url:https://theconversation.com/corbevax-a-new-patent-free-covid-19-vaccine-could-be-a-pandemic-game-changer-globally-174672].
 The vaccine has been approved for distribution in India and Botswana [@url:https://covid19.trackvaccines.org/vaccines/54].
 
-Logistical challenges and geographical barriers also dictate the availability of certain vaccines. 
-Many countries have had poor availability of ultra-low temperature freezers, leading to challenges of distribution for vaccines such as mRNA vaccines that require storage at very low temperatures [@doi:10.1093/inthealth/ihab010; @doi:10.1208/s12249-021-01974-3; @url:https://www.bloomberg.com/news/articles/2021-01-03/pfizer-to-supply-african-health-care-workers-with-vaccines]. 
+Logistical challenges and geographical barriers also dictate the availability of certain vaccines.
+Many countries have had poor availability of ultra-low temperature freezers, leading to challenges of distribution for vaccines such as mRNA vaccines that require storage at very low temperatures [@doi:10.1093/inthealth/ihab010; @doi:10.1208/s12249-021-01974-3; @url:https://www.bloomberg.com/news/articles/2021-01-03/pfizer-to-supply-african-health-care-workers-with-vaccines].
 Furthermore, ancillary supplies such as vaccine containers, diluents for frozen or lyophilized vaccines, disinfecting wipes, bandages, needles, syringes, sharps and biological waste disposal containers are also required, which may not be readily available in geographically isolated locations and can be bulky and expensive to ship [@doi:10.1093/inthealth/ihab010].
 While some of these challenges in vaccine rollout in low- and middle-income countries are being addressed through COVAX [@url:https://www.unicef.org/supply/covax-ensuring-global-equitable-access-covid-19-vaccines], many issues persist worldwide [@doi:10/jqp4; @doi:10.1093/cid/ciac361; @doi:10.1080/20477724.2022.2091862].
 COVAX also failed to distribute its promised two billion vaccine doses on time due to multiple complications [@url:https://www.washingtonpost.com/world/2021/12/10/covax-doses-delivered].
 
-Another major challenge to global vaccine distribution is vaccine hesitancy, which the WHO has designated as a leading global health threat [@url:https://www.who.int/news-room/spotlight/ten-threats-to-global-health-in-2019]. 
+Another major challenge to global vaccine distribution is vaccine hesitancy, which the WHO has designated as a leading global health threat [@url:https://www.who.int/news-room/spotlight/ten-threats-to-global-health-in-2019].
 Polling in the U.S. in January 2021 suggested that 20% of individuals were reluctant to receive a vaccine at that time, with a further 31% expressing some hesitancy to a lesser extent [@url:https://www.kff.org/coronavirus-covid-19/report/kff-covid-19-vaccine-monitor-january-2021; @doi:10.1056/NEJMms2101220].
 A survey of 8,243 long-term healthcare workers in November 2020 (Indiana, USA) reported that only 69% of respondents would ever consider receiving an FDA-approved vaccine due to their perceived risk of side effects (70%), health concerns (34%), efficacy (20%), and religious beliefs (12%) [@doi:10.1111/jgs.17022].
 Notably, almost a third of parents surveyed in the United States in March 2021 expressed concerns about vaccinating their children against COVID-19 [@doi:10.1177/00333549221114346].
-Indeed, vaccine hesitancy has been reported as a significant barrier to vaccine distribution in countries in North and South America, Europe, Asia, and Africa [@doi:10.1002/jmv.28156; @doi:10.1126/sciadv.abm9825; @doi:10.1186/s41256-022-00255-1; @doi:10.1080/20477724.2021.2011580; @doi:10.1136/bmjopen-2021-052432]. 
+Indeed, vaccine hesitancy has been reported as a significant barrier to vaccine distribution in countries in North and South America, Europe, Asia, and Africa [@doi:10.1002/jmv.28156; @doi:10.1126/sciadv.abm9825; @doi:10.1186/s41256-022-00255-1; @doi:10.1080/20477724.2021.2011580; @doi:10.1136/bmjopen-2021-052432].
 Various factors have been associated with increased vaccine hesitancy including access to compelling misinformation via social media [@doi:10.1093/pnasnexus/pgac207; @doi:10.1038/s41591-022-01728-z], religious and conservative political beliefs [@doi:10.1371/journal.pone.0268926; @doi:10.1093/pubmed/fdab122; @doi:10.1177/1075547020960463; @doi:10.1377/hlthaff.2020.02254], and safety and efficacy concerns [@doi:10.1177/00333549221114346], to highlight a few.
 Many of the concerns regarding safety and efficacy have focused on the novel mRNA technologies due to the perceived speed of their development and expedited clinical trial process [@doi:10.1186/s13037-021-00291-9]; however, general vaccine hesitancy relating to traditional vaccine platforms existed long before the pandemic and the distribution of the novel mRNA vaccines [@doi:10.1016/j.vaccine.2015.09.035; @doi:10.1016/j.mayocp.2015.09.006].
 While in the United States, it was hoped that Novavax's Nuvaxovid would appeal to the vaccine hesitant [@url:https://www.ama-assn.org/delivering-care/public-health/what-sets-apart-novavax-option-other-covid-19-vaccines; @url:https://www.galvnews.com/health/free/article_8ddebef4-1db0-579a-b0d2-852f2031d881.html], but this protein subunit vaccine has not led to the uptake hoped [@doi:10.1001/jama.2022.13661; @url:https://www.cnbc.com/2022/07/15/why-new-novavax-covid-vaccine-wont-win-over-unvaccinated-americans.html].
- 
+
 Overall, the vaccine landscape remains heterogeneous even as the pandemic nears its third year, with certain vaccines much more accessible in high-income countries than in low- and middle-income countries.
 The vaccines described in this manuscript, which were developed using well-established technologies, have played a crucial role in improving the feasibility and accessibility of vaccination programs worldwide.
 While the novel technologies have received the bulk of public attention in countries like the U.S., these more traditional vaccine platforms also provide safe and highly effective protection against SARS-CoV-2.
@@ -663,7 +663,7 @@ While the clinical trial efficacy estimates for IWV and subunit have been lower,
 Variation among studies investigating the efficacy of these vaccines, especially CoronaVac, clearly indicate that clinical trials of the same vaccine might not identify the same efficacy, depending on conditions such as the specific variants circulating in a clinical trial population during the trial period.
 Additionally, there are many cohort- and population-level characteristics that can introduce bias within and between clinical trials [@doi:10.1016/j.vaccine.2021.05.099; @doi:10.1093/cid/ciab213], and the extent to which these different factors are present may influence trial outcomes.
 While head-to-head comparisons of VE across different studies may therefore not be appropriate, the results make it clear that effective vaccines have been developed with a wide variety of technologies.
-The vaccines discussed here, which took advantage of well-established approaches, have proven to be especially valuable in pursuing vaccine equity.  
+The vaccines discussed here, which took advantage of well-established approaches, have proven to be especially valuable in pursuing vaccine equity.
 
 ### Conclusions