Response to feedback on novel vaccines

build/assets/custom-dictionary.txt

@@ -615,6 +615,7 @@ Gautret
 Gavi
 GBMF
 gcv
+gdpscatter
 gelsolin
 gemcitabine
 generalizability
@@ -1106,6 +1107,7 @@ ModernaTX
 ModernaTX’s
 Moderna’s
 modRNA
+modularity
 modulatory
 mometasone
 monkeypox
@@ -1685,6 +1687,8 @@ synthetase
 SystemsResearch
 Szeto
 Taguchi
+TAK
+Takeda's
 Tamar
 tamefoxtime
 TaqMan

content/07.pathogenesis.md

@@ -582,6 +582,67 @@ Data and empirically determined biological mechanisms inform models, while model
 Many current efforts to model R~t~ have also led to tools that assist the visualization of estimates in real time or over recent intervals [@url:https://epiforecasts.io/covid; @url:https://rt.live].
 These are valuable resources, yet it is also important to note that the estimates arise from models containing many assumptions and are dependent on the quality of the data they use, which varies widely by region.
 
+### Effect of Vaccines on Pathogenesis and Community Spread
+
+The vaccine clinical trial data demonstrate a significant reduction in the likelihood of contracting symptomatic COVID-19, thereby succeeding in the primary goal of vaccination.
+The mRNA vaccines in particular were initially so effective in preventing disease that they were also assumed to have an effect on the likelihood of transmission (e.g., venues requiring proof of vaccination).
+However, in light of the reduced efficacy in response to VOC, it is especially important to consider whether this assumption is supported by the available evidence.
+
+This question is made up of several components.
+The crux is whether vaccinated individuals with a SARS-CoV-2 infection, regardless of symptom status, are as contagious as unvaccinated, infected individuals.
+Additionally, as outlined above, an important qualification is that the variants of SARS-CoV-2 circulating at the time of each study must be considered in light of the effect of evolution on vaccine efficacy.
+
+The phase II/III clinical trials evaluating the mRNA vaccines assessed vaccine efficacy based on COVID-19 diagnosis, thereby detecting only patients who received a diagnosis.
+In order to identify patients infected with SARS-CoV-2 who did not receive a diagnosis, for example, potentially those who did not develop symptoms, it would be necessary to conduct routine PCR testing even in the absence of symptoms. <!-- Define PCR? -->
+Prior to the development of vaccines, the evidence suggested that asymptomatic individuals could spread SARS-CoV-2.
+Investigation of viral dynamics of asymptomatic infection in early 2020 indicated that asymptomatic patients continued to shed the virus for a duration similar to that of symptomatic patients [@doi:10.1016/j.ijid.2020.05.030] (although viral shedding should not be conflated with contagiousness without further investigation).
+Another study found viral load to be higher in the nasopharyngeal/oropharyngeal samples of asymptomatic patients compared to symptomatic patients hospitalized due to symptoms and/or known exposure [@doi:10.1007/s15010-020-01548-8].
+However, the sample size in both of these studies was small, and a larger study found higher viral load in symptomatic than asymptomatic cases [@doi:10.3390/v13020304] along with a systematic review finding a reduced probability of asymptomatic transmission [@doi:10.3138/jammi-2020-0030].
+While far from conclusive, these studies suggest that asymptomatic cases still cary a risk of transmitting SARS-CoV-2.
+
+One important consideration is therefore how likely vaccinated individuals are to develop asymptomatic SARS-CoV-2.
+Considering asymptomatic cases is necessary to establish a more complete picture of efficacy with respect to spread.<!-- To Do: Possible figure indicating pyramid of risk with and without vaccines?-->
+Routine testing of healthcare workers in California who had received an mRNA vaccine revealed slightly higher rates of absolute risk for testing positive than those identified in the phase II/III trials, although the extent to which asymptomatic infection influenced these numbers was not investigated [@doi:10.1056/NEJMc2101927].
+Another study analyzed the results of COVID-19 screening tests administered to asymptomatic individuals prior to receiving certain medical services at the Mayo Clinic in several locations across the United States.
+This study found patients who had received two doses of an mRNA vaccine to be 73% less likely to have asymptomatic COVID-19 than patients who had received zero doses [@doi:10.1093/cid/ciab229].
+Because this study began on December 17, 2020, a date selected to coincide with the first day vaccines were available at the Mayo Clinic, this number may underestimate the efficacy of the vaccines given that many people eligible for early vaccination were at increased risk for exposure (e.g., healthcare workers and residents of long-term care facilities) [@doi:10.1093/cid/ciab229].
+In Israel, a longitudinal study of nearly 12,000 healthcare workers found that of the 5,372 fully vaccinated people with Pfizer/BioNTech BNT162b2, 8 developed symptomatic COVID-19 (0.15%) and 19 developed asymptomatic COVID-19 (0.35%) [@doi:10.1001/jama.2021.7152].
+While the study itself analyzed the efficacy of the vaccine based on person-days, these findings also suggest that many or even the majority of SARS-CoV-2 infections in vaccinated individuals are likely to be asymptomatic.
+Therefore, in addition to the symptomatic cases reported by the vaccine clinical trials, these findings suggest that asymptomatic cases can also occur in vaccinated people.
+In the absence of symptoms, individuals are less likely to know to self-isolate, and therefore evaluating the effect of the vaccine on viral load is critical to understanding the role vaccinated individuals can play in spreading SARS-CoV-2.
+
+Another question of interest is therefore whether vaccinated individuals positive for SARS-CoV-2 carry a similar viral load to unvaccinated individuals.
+Viral load is often approximated by cycle threshold (C~t~), or the cycle at which viral presence is detected during RT-qPCR, with a lower C~t~ corresponding to a greater viral load.
+A prospective cohort study that evaluated front-line workers in six U.S. states from December 2020 to April 2021 reported a 40% reduction in viral load even with just a single dose of an mRNA vaccine [@doi:10.1056/nejmoa2107058].
+The vaccine also appeared to influence the time to viral clearance: the risk of having detectable levels of SARS-CoV-2 for more than one week was reduced by 66% in participants who had received at least one dose [@doi:10.1056/nejmoa2107058].
+However, this study compared the mean viral load across the two groups, meaning that these findings cannot be extrapolated across all points in the disease course.
+Similarly, between December 2020 and February 2021, positive RT-qPCR tests were analyzed for almost 5,000 Israeli patients [@doi:10.1038/s41591-021-01316-7].
+C~t~ was analyzed relative to when each patient received the first dose of the Pfizer mRNA vaccine.
+A sharp increase in C~t~ (corresponding to reduced viral load) was observed between days 11 and 12, consistent with what is known about the onset of immunity following vaccination.
+This pattern therefore suggested a direct effect of vaccination on viral load.
+
+Other studies, however, have not offered support for a reduced viral load in breakthrough cases.
+In Singapore, which has strict protocols for screening individuals with potential COVID-19 exposure, a retrospective cohort of patients who tested positive for SARS-CoV-2 between April and June 2021 was analyzed to compare viral kinetics and symptom course between vaccinated and unvaccinated cases.
+Vaccinated individuals who tested positive experienced fewer symptoms than unvaccinated, SARS-CoV-2-positive individuals and were more likely to be asymptomatic [@doi:10.1101/2021.07.28.21261295].
+Additionally, this study analyzed C~t~ over time and found that, though the median values were similar between the two groups at disease onset, viral load appeared to decrease more rapidly in vaccinated cases [@doi:10.1101/2021.07.28.21261295].
+This study is likely to have evaluated a more accurate representation of all COVID-19 outcomes than has been feasible in most studies, but one limitation was that the RT-PCR reactions were conducted in many different facilities.
+A third study investigated viral load (as approximated by C~t~) using samples processed in a single laboratory during the summer of 2021 [@doi:10.1101/2021.07.31.21261387].
+This study identified no significant differences in C~t~ between fully vaccinated and unvaccinated cases, but this study used samples sent for diagnosis and was not longitudinal.
+It offered the additional benefit of culturing samples to assess whether their C~t~ threshold was likely to represent contagiousness and found that SARS-CoV-2 could be cultured from 51 of 55 samples with C~t~ less than 25 (the cut-off used in many studies).
+Another study of samples collected at two sites in San Francisco, one of which tested only asymptomatic individuals, reported no difference in C~t~ between asymptomatic and symptomatic cases regardless of whether vaccination status was included in the model [@doi:10.1101/2021.09.28.21264262].
+Though each of these three studies offers distinct strengths and weaknesses, taken together, they suggest that viral load is likely to be similar in vaccinated and unvaccinated individuals, but that vaccinated individuals clear the virus more rapidly, meaning that the average viral load is lower over time.
+
+Given the emergence of VOC, especially the Delta and Omicron variants, for which breakthrough infections are more common, the potential for vaccinated individuals to spread SARS-CoV-2 is not static over time.
+In fact, studies reporting reduced viral load in vaccinated individuals collected samples, for the most part, prior to the emergence of the Delta variant's dominance.
+The emergence of this variant may partially account for why more recent studies tend to find no difference between viral load in vaccinated and unvaccinated cases.
+
+Taken together, these findings can provide some insight into how vaccines influence community spread.
+While vaccinated individuals may be more likely to experience asymptomatic infection, current evidence about viral load in asymptomatic versus symptomatic cases is ambiguous.
+Similarly, no conclusions can be drawn about whether viral load is different in vaccinated versus unvaccinated cases.
+Therefore, at present, the evidence suggests that vaccinated individuals who are infected can still contribute to community spread.
+The one potential mitigating factor supported at present is that differences in the viral kinetics may result in vaccinated cases infecting fewer individuals over time due to a more rapid decrease in viral load [@doi:10.1101/2021.07.28.21261295], although this study did not examine patterns in secondary transmission.
+Thus, the virological evidence suggests that public health measures such as masking and distancing remain important even in areas with high vaccination rates.
+
 ### Conclusions
 
 The novel coronavirus SARS-CoV-2 is the third HCoV to emerge in the 21st century, and research into previous HCoVs has provided a strong foundation for characterizing the pathogenesis and transmission of SARS-CoV-2.

content/22.vaccines-trad.md

@@ -44,7 +44,7 @@ We review vaccine technologies used for SARS-CoV-2 in two parts: here, the appli
 
 Understanding vaccine development programs that are using well-established technologies is important for a global perspective on COVID-19.
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-A resource tracking the distribution of {{owid_vaccine_counts}} vaccines indicates that, as of {{owid_most_recent_date}}, {{owid_total_vaccinations}} doses have been administered across {{owid_total_countries}} countries [@doi:10.1038/s41562-021-01122-8].
+A resource tracking the distribution of {{owid_vaccine_counts}} vaccines indicates that, as of {{owid_most_recent_date}}, {{owid_worldwide_total_vaccinations}} doses have been administered across {{owid_total_countries}} countries [@doi:10.1038/s41562-021-01122-8].
 Many of these vaccines use platforms that do not require information about the viral genome, with {{viper_num_approved_subunit}} developed using subunit and {{viper_num_approved_whole_virus}} using whole-virus approaches.
 The types of vaccines available varies widely throughout the world, as the process of developing and deploying a vaccine is complex and often requires coordination between government, industry, academia, and philanthropic entities [@doi:10.1126/science.abc5312].