A CLOSER LOOK AT COVID-19 VACCINES: THE KNOWN, THE
A CLOSER LOOK AT COVID-19VACCINES: THE KNOWN, THEUNKNOWN, AND THE UNCERTAINK2P COVID-19 SeriesFull Product
AUTHORSNadeen Hilal, Nada Melhem, Fadi El-JardaliACKNOWLEDGEMENTThe authors would like to thank Ms. Clara Abou Samra for documentreview and design, Ms. Nour Ataya and Ms. Lama Bou Karroumfor document review, and Ms. Rayane Nasreddine for the Arabictranslation.CITATIONHilal N, Melhem N, El-Jardali F. K2P COVID-19 Series: A Closer Lookat COVID-19 Vaccines: The Known, the Unknown, and the Uncertain.Knowledge to Policy (K2P) Center, Beirut, Lebanon, February 10,2021
AIMSince its onset in December 2019, the COVID-19 pandemic has disrupted the world,with a heavy toll on human lives and economic activities. The COVID-19 pandemicis believed to be the largest global public health crisis in a century (UNFPA, 2020)and has been described as the greatest challenge experienced since World WarTwo (UNDP, 2020). As a result, rapid development of an effective and safe vaccinebecame a global imperative. After an unconventionally expedited productiontrack, COVID-19 vaccines have arrived, and with them the biggest vaccinationcampaign in history has begun. As of February 9th, 2021, more than 134 millionvaccine doses in 73 countries have been administered (Bloomberg, 2021). InLebanon, the first batch of COVID-19 vaccines is expected to arrive during the firsthalf of February 2021. Preparations are underway for optimal vaccine deployment.The plan includes details on set priority groups, deployment centers, and otherrelated instructions (MOPH, 2021).Despite the societal upheaval the pandemic has triggered, and the hopes builton the COVID-19 vaccines, considerable vaccine hesitancy has been witnessed.A study from Arab countries reported that the general public acceptance rate forCOVID-19 vaccines was only 29.4% (Sallam et al., 2021). In Lebanon, based on theresults of an unpublished study employing social media surveys, a substantialproportion (79%) of the Lebanese population has shown hesitancy towards theCOVID-19 vaccines (Halabi et al., submitted article). Both conspiracy theories (Ball& Maxmen, 2020) and misinformation (Lockyer et al, 2020) lie at the very base ofvaccine hesitancy. Additionally, considerable ambiguity remains in relation todifferent aspects and characteristic of COVID-19 vaccines.The aim of this product is to present the latest evidence on COVID-19 vaccines.The aim is not to advocate for or against COVID-19 vaccines in general or aspecific COVID-19 vaccine, but rather to present the known, the unknown, and theuncertain. Information in this product can also serve as a base for informationalcampaigns, thereby promoting mindful and informed decision-making. Theevidence presented in this product is based on the evidence available by February10, 2021.K2P COVID-19 SERIESA CLOSER LOOK AT COVID-19 VACCINES: THE KNOWN, THE UNKNOWN, AND THE UNCERTAIN3
COVID-19 VACCINES AVAILABLE FORPUBLIC USEUntil February 2nd 2021, 63 candidate vaccines are undergoing clinical evaluationwith 177 other candidate vaccines in the preclinical evaluation phase (WHO, 2020).A summary of characteristics of vaccines in public use is presented in the Table 1(WHO, 2020; Observer, 2020; BBC, 2021; Reuters, 2020a; Fierce Pharma, 2020; FDA,2020b; FDA, 2020c, Zhang et al., 2020; Zhu et al., 2020; Xia et al., 2020; Logunov etal., 2021). Further details related to indication, administration, efficacy, and safetyof vaccine are presented in the following sections of this product.SELECTION PROCESSA comprehensive search of the literature was undertaken toidentify articles focusing on the topic of COVID-19 vaccines.Search strategy consisted of reviewing the following databases:Medline/Pubmed (MeSH term: Coronavirus Infections and ViralVaccines; keywords: COVID-19 vaccine, coronavirus vaccine),IMEMR (keywords: COVID-19 vaccine, coronavirus vaccine),Health Evidence (keywords: COVID-19 vaccine, coronavirusvaccine), and Embase (keywords: COVID-19 vaccine, coronavirusvaccine). In addition, data retrieved from grey literature websitesincluding WHO, FDA, CDC, clinical trials, websites of professionalgroups, media websites, and others were included. Articlesand data sources included in this product where those thatfocused on COVID-19 vaccine characteristics including efficacy,safety, indications, and administration. Handsearching was alsoperformed with two objectives: 1) searching for supporting dataand 2) conducting fine searches. As a result of this methodology,84 articles and data sources were included in this product.4K2P COVID-19 SERIESA CLOSER LOOK AT COVID-19 VACCINES: THE KNOWN, THE UNKNOWN, AND THE UNCERTAIN
K2P COVID-19 SERIESA CLOSER LOOK AT COVID-19 VACCINES: THE KNOWN, THE UNKNOWN, AND THE UNCERTAIN5
Table 1: COVID-19 Vaccines Available for Public UseCOVID-19Vaccine ermRNABioNTech(USA)Number,Route, &Timing ofdosesStorageIndications2 IM doses-70oC for 6 16 yearsseparated by months and of age and21 days2-5oC for up olderto 5 daysModerna(USA)mRNA2 IM doses-20oC for 6 18 yearsseparated by months and of age and28 days2-8oC for 30 olderdaysAstraZenecaOxford(UK)Non-ReplicatingViral VectorAdenoviral vectorbased platform2 IM dosesStandard18 yearsseparated by refrigeration of age and29 dard18 years2 IM dosesseparated by refrigeration of age andolder14 days or 28 al VectorAdenoviral vectorbased platform2 IM dosesStandard18 yearsseparated by refrigeration of age and21 ngViral VectorAdenoviral vectorbased platform1 IM injection Standard18 yearsrefrigeration of age and2-8oColderSinopharm(China)Inactivated2 IM dosesStandard18 yearsseparated by refrigeration of age and21 days2-8oColder6K2P COVID-19 SERIESA CLOSER LOOK AT COVID-19 VACCINES: THE KNOWN, THE UNKNOWN, AND THE UNCERTAIN
erBioNTech(USA)ClaimedEfficacy(Type oftrial)Moderna(USA)33 per dose94.1%Pain at the injection site,(Phase 3) tiredness, headache, musclepain, chills, joint pain, swollenlymph nodes in the same armas the injection, nausea andvomiting, and fever4 per dose70.4%Pain at the injection site,(Phase 3) fatigue, headache, muscle ache,malaise, feverish, chills, jointpain; reported for participantswho received 2 doses ofvaccine; adverse events wereless frequent in older adults30 per dose50.4Pain at the injection site91.75%No serious adverse events and(Phase ½) no common adverse events at 25% a)Common Side Effects95%*Pain at the injection site,(Phase 3) tiredness, headache, musclepain, chills, joint pain, and feverApproximatePrice20 per doseGamaleyaSputnik(Russia)91.6%Pain at the injection site,7.5 per dose(Phase 3) changes in laboratory variables,hyperthermia, headache,asthenia, muscle or joint pain,palpitationCanSinoBiologics(China)NotPain at the injection site, fatigue, Not reportedreported fever, headacheSinopharm(China)79-86%*(Phase1/2)No reported local side effects,no serious side effects, and nocommon adverse events at 25% prevalence72.5 per dose* For more details, check section titled ‘Alterations and Concerns Regarding Reported Efficacy’
01EFFICACY OF COVID-19 VACCINESDELINEATION OF THE CONCEPT OF EFFICACYPhase 3 vaccine trials are designed to assess individual-level efficacyand safety. These trials typically focus on the endpoint of laboratoryconfirmed, symptomatic disease to capture the direct benefit ofthe vaccine and form the basis for regulatory decisions. However, asafe and effective vaccine could help to protect communities in twodistinct ways (Lipstich & Dean, 2020):Direct Protection8Indirect ProtectionHigh-risk groups arevaccinated to prevent diseaseThose in contact with high-riskindividuals are vaccinated toreduce transmissionAbility of vaccine to protecthigh-risk groups can bemeasuredAssessment of the ability ofa vaccine to protect high-riskgroups is challengingK2P COVID-19 SERIESA CLOSER LOOK AT COVID-19 VACCINES: THE KNOWN, THE UNKNOWN, AND THE UNCERTAIN
In addition, a candidate vaccine againstCOVID-19 might act to protect frominfection, disease, or death. As such, avaccine capable of reducing any of theseelements could contribute to diseasecontrol. Vaccines that act to reducethe transmissibility of COVID-19, arevaluable interventions at the populationlevel (Hodgson et al., 2020).With the AstraZeneca-Oxfordvaccine, the overall number ofcases of any positive PCR wasreduced by 67% after a singledose, suggesting the potentialfor a substantial reduction intransmission (Voysey et al.,2021).Adopted from Hodgson et al., 2020ALTERATIONS AND CONCERNS REGARDING REPORTED EFFICACYInitial reports of COVID-19 vaccines efficacy have been very promising, witha significant number of vaccines reporting efficacies above 90% (Table 1),much higher than the 50% cutoff needed for authorization (FDA, 2020a).However, with vaccine rollout, there has been changes in some of thereported vaccine efficacies, while concerns were raised with others, assummarized in the table below. It should be noted here that more accurateinformation will be hopefully revealed in the future from real-life phase 4or long-term observational studies.K2P COVID-19 SERIESA CLOSER LOOK AT COVID-19 VACCINES: THE KNOWN, THE UNKNOWN, AND THE UNCERTAIN9
Table 2: Alterations and Concerns Regarding Reported EfficacySinovacSinopharmInterim data from late-stage phase 3 trials in various countries(BBC, 2021): Turkey reported 91.25% efficacy Indonesia reported 65.3% efficacy Brazil initially claimed that was 78% effective, but in January2021 revised the figure to 50.4% after including more datain their calculationsThe efficacy of the Sinovac vaccine have been viewed withsome skepticism as results were published via press releasesrather than a peer-reviewed data, which makes it difficult toassess validity of results (BBC, 2021). Announced on December 30th that phase 3 trials of thevaccine revealed an efficacy of 79% The United Arab Emirates reported that the vaccine was86% efficacious, according to interim results of its phase 3trial (BBC, 2021).GemalyaSputnik VBefore publishing the results of phase 3 trials, the journey ofthe Sputnik V vaccine was characterized by concern due to thelack of transparency on the results of preclinical and clinicaltrials (Balakrishnan, 2020; Bucci et al., 2020). Prematureapproval, granted before the initiation of phase 3 trials or thedissemination of the results of earlier stage trials was believedto entail numerous risks (Burki, 2020; Caddy, 2020).PfizerBioNtechConcerns of inappropriate trial statistical calculation through: Ignoring of suspected cases of COVID-19 Excluding more patients due to major protocol deviation inthe vaccine group as compared to control groupAs per an opinion article, this may have resulted in heightenedefficacy results. Also, according to the article, a rough estimateof vaccine efficacy against developing COVID-19 symptomswould be a relative risk reduction of 19-29%, which is farbelow the 50% effectiveness threshold for authorization(Doshi, 2021).AstraZeneca- The German government challenged the efficacy reportsOxfordof the Oxford-AstraZeneca vaccine for older people, statingthat the efficacy may be below 10% for this population (TheGuardian, 2021).10K2P COVID-19 SERIESA CLOSER LOOK AT COVID-19 VACCINES: THE KNOWN, THE UNKNOWN, AND THE UNCERTAIN
TIMING OF PROTECTIONThe exact timing of protection initiation postCOVID-19 vaccine is still uncertain. Despiteevidence of protection as early as 12 days withthe Pfizer-BioNtech vaccine (Polack et al., 2020)and 14 days with the Moderna vaccine (Badenet al., 2021), the general understanding is thatit takes few weeks for the immune system torespond to the vaccine and provide protectionagainst the infectious disease (CDC, 2021a).DURATION OF PROTECTIONThe duration of protection of COVID-19 vaccineis still yet to be determined. Preliminaryevidence suggests waning antibody titers inthose who have recovered from COVID-19infection (Ward et al, 2020). Early data from theModerna vaccine suggested that neutralizingantibodies persisted for around 4 months withtiters declining slightly over time (Jackson etal., 2020). However, effectiveness and durationof protection are to be identified followingvaccination in real-life settings.Antibodiesare protectiveproteinsproduced by theimmune systemin response tothe presence of aforeign body or avaccine.PROTECTION AGAINST THE NEW COVID-19 VARIANTSWith the emergence of new variants of COVID-19, the scientific communitywas reassured that since vaccines produce polyclonal antibodies thattarget several parts of the spike protein, the virus would likely need toaccumulate multiple mutations to evade immunity induced by vaccines orby natural infection (CDC, 2020a). However, more recently, there is growingconcern that some coronavirus variants could eventually evade immuneresponses triggered by vaccines and previous infections (Callaway, 2021).In addition, some preliminary studies suggest that some vaccines may bemore protective against some of the strains than others (Shi et al., 2021;Wibmer et al., 2021; Wang et al., 2021).K2P COVID-19 SERIESA CLOSER LOOK AT COVID-19 VACCINES: THE KNOWN, THE UNKNOWN, AND THE UNCERTAIN11
SUBGROUPS VACCINE EFFICACYPhase 3 vaccine trials are designed to assess individual-level efficacy andsafety. Despite that some subgroup differences were noted in phase 3COVID-19 vaccines trials, inferences cannot be made with confidence.Of particular interest are the high-risk subgroups, such as the olderpopulation. One way to address efficacy in this population is by settingminimum enrollment targets for older adults (Lipstich & Dean, 2020). Asrevealed below, reviewing the baseline characteristics of participants inthree phase 3 trials, it was noted that there was substantial variation in theproportion of older population participation.Moderna25% of trialparticipants wereolder than 65 years(Baden, 2021)12K2P COVID-19 SERIESPfizerBioNtechAstraZenecaOxford42% of trialparticipants wereolder than 55 years(Polack et al., 2020)4% of trialparticipants wereolder than 69 years(Voysey, 2020)A CLOSER LOOK AT COVID-19 VACCINES: THE KNOWN, THE UNKNOWN, AND THE UNCERTAIN
Thus, to assess efficacy with some degree of certainty, high-risk groups, i.e.,those for whom the vaccine is primarily designed to protect, should be wellrepresented in any vaccine trial. Post-approval observational studies shouldalso ensure significant inclusion of the older population. Similarly, conclusionscannot be drawn with confidence for other sub-groups such as pregnantwomen and the immunocompromised unless satisfactory participation inclinical trials is guaranteed.K2P COVID-19 SERIESA CLOSER LOOK AT COVID-19 VACCINES: THE KNOWN, THE UNKNOWN, AND THE UNCERTAIN13
02SAFETY OF COVID-19 VACCINESCOMMON ADVERSE EFFECTSThe scientific literature has been generally reassuring regardingserious side effects of COVID-19 vaccines. The vast majorityof side effects of COVID-19 vaccines are comparable to thoseof other well-known vaccines. These typically occur in the firstfew days post vaccination and include local reactions, fever,headache, muscle pains, and fatigue (Table 1).14K2P COVID-19 SERIESA CLOSER LOOK AT COVID-19 VACCINES: THE KNOWN, THE UNKNOWN, AND THE UNCERTAIN
SERIOUS SIDE EFFECTS OF COVID-19 VACCINESA number of concerns have been raised of other more serious side effects.Some associations were denied, while others need more time and furtherstudies to determine causal associations. A summary of safety findings ispresented below: Bell’s palsy was reported morefrequently in mRNA vaccinerecipients than in controls, butthere was not a sufficiently largenumber of cases to concludethat this was beyond whatwould naturally be observed inpopulations of this size by chance(CDC, 2020c).No increased occurrence ofGuillain-Barre syndrome wasdetected (CDC, 2020c).Three cases of transverse myelitisoccurred following vaccination withthe AstraZeneca-Oxford vaccine,one of which occurred 14 daysafter the second dose while theALLERGY AND ANAPHYLAXISThe rates of anaphylaxis (severeallergic reaction) were 5 cases permillion with the Pfizer-BioNtechvaccine and 2.8 cases per millionwith the Moderna vaccine(Reuters, 2021b).two other cases were consideredto be unlikely related to the vaccine(Knoll et al, 2021). No association has been provenyet with immune enhancement(Flanagan et al., 2020) or femalefertility problems (WebMD, 2021),despite ongoing deliberations. Bell’s palsy is a condition that causestemporary weakness or paralysis of themuscles in the face. Guillain-Barre and transverse myelitisare autoimmune neurological diseasesresulting in weakness. Immune enhancement, also knownas immune backfiring, occurs whencomponents of the immune system thatusually protect against viral infectionsend up backfiring.Anaphylaxis is a serious allergic reaction to a triggerthat results in symptoms including rash, facialswelling, dizziness, and difficulty breathing.K2P COVID-19 SERIESA CLOSER LOOK AT COVID-19 VACCINES: THE KNOWN, THE UNKNOWN, AND THE UNCERTAIN15
DEATH OUTCOMEThe most important efficacy endpoint, protection against severe disease anddeath, is difficult to assess in phase 3 clinical trials (Hodgson et al., 2020). So far,it is still unknown whether any of the developed vaccines confers protectionagainst COVID-19 mortality. On the other hand, there were reports of about30 deaths in over 40,000 elderly individuals in Norway vaccinated with thePfizer-BioNTech vaccine. The deaths were recorded among very frail patients,including some who were anticipated to only have weeks or months to live. Thedeaths were associated with fever, nausea and diarrhea (TGA, 2021), which arecommon side effects of the vaccine. This report questioned whether the PfizerBioNtech vaccine is an appropriate choice for the elderly, very frail patients.16K2P COVID-19 SERIESA CLOSER LOOK AT COVID-19 VACCINES: THE KNOWN, THE UNKNOWN, AND THE UNCERTAIN
NEED FOR LONG-TERM SAFETY DATAPrevious experience with other vaccines has taught us that despite their verylow frequency, some side effects can be major while others might happenseveral months post-vaccination. Examples of such reactions are presentedbelow (WHO, 2010; WHO, 2004; WHO, 2003; WHO, 2005; WHO, 2009):Table 3: Serious and Long-Term Side Effects of Common VaccinesVaccineReactionOnset intervalFrequency per dosegivenBCGFatal disseminationof BCG infection1-12 months0.19-1.56/1,000,000OPVVaccine associatedparalyticpoliomyelitis4-30 days2-4/1,000,000DTwPProlonged crying and 0-24 hoursseizures 1/100HHE0-24 hours 1/1,000 – 2/1,000Febrile seizures6-12 days1/3,000Thrombocytopenia15-35 days1/30,000MeaslesBCG: Bacillus Calmette-Guérin (vaccine against Tuberculosis)OPV: Oral Polio VaccineDTwP: Diphtheria, Tetanus, whole cell inactivated PertussisHHE: Hypotonoic Hyporesponsive EpisodeGiven the novelty of the COVID-19 vaccines and in the absence of long-termfollow-up data, the probability of long-term adverse effects, despite likely to below, cannot be nulled.K2P COVID-19 SERIESA CLOSER LOOK AT COVID-19 VACCINES: THE KNOWN, THE UNKNOWN, AND THE UNCERTAIN17
CONCERNS REGARDING TECHNOLOGY USEDSafety concerns have been raised regarding some of the technologies used forthe development of COVID-19 vaccines, namely the use of adenovirus-vectoredvaccines and mRNA. The currently available knowledge on these subjects issummarized below.Use of Adenovirus-vectored VaccinesSome vaccines rely on using an adenoviral vector to deliver a DNAmolecule that encodes the COVID-19 spike protein. Vaccines which haveadopted this technology include the vaccines produced by CanSino,AstraZeneca-Oxford, and Gamaleya. Despite the reported efficacy andsafety of several recombinant adenovirus vaccines (Zhu e
K2P COVID-19 SRIS A CLOSER LOOK AT COVID-19 VACCINES: THE KNOWN, THE UNKNOWN, AND THE UNCERTAIN 3. COVID-19 VACCINES AVAILABLE FOR PUBLIC USE Until February 2nd 2021, 63 candidate vaccines are undergoing clinical evaluation with 177 other candidate
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