Friday, December 19, 2014

Forget whether it matches, just get your vaccine! / CDC

CDC has created a litany of excuses for why it recommends flu vaccines for kids despite poor protection against the two strains of influenza A (H1N1 and H3N2). See below for the data on the poor vaccine match this year. Below are the reasons CDC says parents should still give the current vaccine to their children.  I read between the lines after each one.
"... Because: 
1. Surveillance shows that there is substantially more circulation of influenza A (H3N2) and B viruses and very little circulating H1N1 so far; (i.e., the strain for which there is zero effectiveness is only a minor problem--Nass)
2. LAIV has been shown to offer good protection against influenza A (H3N2) and influenza B viruses in the past; (forget the antigenic drift problem and focus on past success--Nass)
3. LAIV may offer better protection than IIV against antigenically drifted viruses that may circulate this season; (compare one poor vaccine to another poor vaccine against drifted H3N2, to emphasize a possible, marginal benefit--Nass)
4. Vaccine providers have received their vaccine for the 2014-2015 season and have likely administered a good proportion of it; (create fear of a shortage to increase vaccine uptake--Nass)
ACIP and CDC have not changed the current influenza vaccination recommendations. (They never do, regardless of the match between flu strains and vaccines--Nass)
People who have not been vaccinated yet this season should get vaccinated now. Parents should seek to get their children immunized with whatever vaccine is immediately available and indicated..." (By all means, don't postpone vaccinations until learning whether this year is a good match--Nass)

Thursday, December 18, 2014

NYC forcing youngest residents to receive poorly effective flu vaccines--or goodbye daycare!

NYC's unelected health department demanded last December that children aged 6 months to 5 years receive yearly flu vaccinations. This was one of outgoing mayor (and newly minted health expert) Michael Bloomberg's gifts to the city, along with the banning of extra large soft drinks.

Are soft drinks a threat to others?  What right has any government to ration their consumption? Overreaching in the name of public health has become a stock-in-trade of politicians.

Some officials glory in their power to compel.  Others do so to earn political points. (Think of Maine's Governor Paul LePage, who insisted on quarantining nurse Kaci Hickox, despite several negative tests for Ebola and no symptoms. He soon won a tight re-election race.)

Only two states require flu shots for children:  New Jersey and Connecticut.  NJ's deputy health commissioner Eddy Bresnitz left to become Medical Director of Merck Vaccines soon after imposing vaccine mandates on NJ's children. He followed the same trajectory as former CDC Director, Julie Gerberding, who became President of Merck Vaccines after leaving CDC.  Merck bankrolled Texas Governor Perry's preteen HPV vaccine mandate, as well as dozens of legislative initiatives.  Merck pays Dr. Gregory Poland, who has worked tirelessly to impose flu vaccine mandates.

The word has just gone out about enforcement in NYC: vaccinate your kids or goodbye day-care! Parents must submit proof of vaccination before the end of 2014.

But right now, the vaccinations don't work against 66% of circulating flu strains!  (See details below.) Last year, the nearly exclusive flu bug was H1N1, and the vaccine for kids did not work against it.  

So for both flu seasons since NYC imposed a mandate, the shots for kids have been practically useless. But unfortunately, that did not reduce their side effects. You got the risk without the benefit. Did the NYC health department blink?  Of course not.

Why demand these vaccinations now? Especially since harsh enforcement measures were not supposed to start until 2016.

It only makes sense from the manufacturers' and CDC's point of view: flu shots are a means of transferring (mostly public) funds to pharmaceutical companies, and they are CDC's main raison d'etre.  CDC can't handle its dangerous germs, or recommend the right gear for healthcare workers fighting Ebola, but its flu vaccine campaigns are examples of superb PR. Note the repetitive CDC pronouncements about children dying from flu, such as this one. Though this unfortunate toddler died despite her flu vaccination.

This December, according to CDC, 3 strains of flu predominate. They are influenza A H3N2 (90% of the total), Influenza A H1N1 (5% of the total) and Influenza B (5% of the total). Vaccines have 3 or occasionally 4 components directed against these strains.

But 67.5% of the H3N2 tested 2 weeks ago has mutated, so the H3N2 component of the vaccine is not very effective. The majority of flu vaccine used in children (the nasal spray) also has an H1N1 component that is not effective.  The influenza B part of the vaccine seems to be effective, but influenza B only accounts for 5% of flu strains. 

The injected vaccine may be effective against influenza A H1N1 virus also.  That might bump it up to 40% effective, in the test tube.

But wait:  even when a flu vaccine matches the circulating strains 100%, it is only found to be 50-70% effective at preventing flu in recipients.  So a 40% match could correspond to a 25% degree of effectiveness.  We won't find out for sure till the season is over.  According to CDC: 
"... even during years when the vaccine match is very good, the benefits of vaccination will vary across the population, depending on characteristics of the person being vaccinated and even, potentially, which vaccine was used."

In vitro, 53 existing *licensed* drugs have activity against Ebola virus entry into cells/ Emerging Microbes and Infections, a Nature publication

Yesterday, authors from the NIH, NY and Toronto published a paper describing their screening system for compounds against Ebola.  The method has identified a large number of approved substances with potential benefits. Many of them have been mentioned in this blog previously, such as clomifene, antimalarials and antiarrhythmics.  Ninety-five additional compounds were also found to have in vitro activity against Ebola, but are not licensed drugs.

One weakness of this paper is the absence of comparison of the therapeutic drug level for anti-Ebola activity, compared to the drug level needed for other therapeutic effects. Some of the active drugs found, such as digoxin and anticancer drugs, have narrow therapeutic to toxic windows, whereas other anti-Ebola drugs found, such as antihistimines, have wide therapeutic to toxic ratios and are likely to be well tolerated, even in patients with extremely unstable conditions.  

Now rapid animal testing is needed and then hopefully careful human clinical trials can commence.  It is exciting that many disciplines have turned their spotlights (and tool chests) on the myriad problems that need to be solved to conquer to Ebola epidemic.



Identification of 53 compounds that block Ebola virus-like particle entry via a repurposing screen of approved drugs

Jennifer Kouznetsova, Wei Sun, Carles Martínez-Romero, Gregory Tawa, Paul Shinn, Catherine Z Chen, Aaron Schimmer, Philip Sanderson, John C McKew, Wei Zheng and Adolfo García-Sastre

Table 1. Twenty-three active compounds that block Ebola VLP entry into HeLa cells.

Drug NameBlock Ebola VLP entryCytotoxicitySelectivityApproved indicationMOA
IC50(µM)IC90(µM)Max. Inh. (%)IC50 (µM)Index (fold)
Vinblastine0.0480.13087>500>10 324AnticancerMicrotubule inhibitor
Vinorelbine/Navelbine0.0660.19090>500>7546AnticancerMicrotubule inhibitor
Vincristine0.1410.25883>500>3554AnticancerMicrotubule inhibitor
Colchicine0.2380.35473>500>2097Primary for goutMicrotubule inhibitor
Nocodazole*0.4021.0487>500>1242AnticancerMicrotubule inhibitor
Toremifene0.5663.7398180316AnticancerEstrogen receptor modulator
Tamoxifen0.7343.159799.8135AnticancerEstrogen receptor modulator
Digoxin0.7633.4568250327AntiarrhythmicNa+-K+ pump inhibitor
Clemastine1.103.769895.687Antiallergic, hay fever, rhinitisHistamine antagonist
Raloxifene/Evista1.849.01100>500>271AnticancerEstrogen receptor modulator
Sunitinib1.913.829014877AnticancerKinase inhibitor
Thiothixene1.927.1810070.136AntipsychoticDopamine antagonist
Dronedarone2.203.518148.021AntiarrhythmicMultichannel blocker
Maprotiline2.4412.110014660AntidepressantAdrenergic uptake inhibitors and histamine antagonist
Daunomycin2.635.4098>500>190AnticancerTopoisomerase Inhibitor
Benztropine2.648.2510025095Anticholinergic, antihistamineHistamine antagonist and Cholinergic antagonist
Azithromycin2.7915.8100>500>179AntimicrobialProtein synthesis inhibitor
Mebendazole3.4414.088>500>145AntihelminthicMicrotubule inhibitor
Trifluoperazine4.4812.09797.021Antipsychotic, antiemeticDopamine antagonist
Clarithromycin4.5315.1100>500>110AntimicrobialProtein synthesis inhibitor
Albendazole4.9020.776>500>102AnthelminticMicrotubule inhibitor
Clomipramine4.9911.79364.112AntidepressantSerotonin uptake inhibitors and histamine antagonist
Propafenone6.2523.8100>500>80AntiarrhythmicSodium channel blocker
 Abbreviations: MOA, mechanism of action; IC90, inhibitory concentration of 90%; Max. Inh., maximal inhibition.
* The compound was not the original hit but was added for confirmation.
 These compounds were previously reported to be active in Ebola assays.

Table 2. An additional 30 active compounds that block Ebola VLP entry in our assay at an IC50<10 and="" nbsp="" si="">10 plus three additional active compounds previously shown to inhibit Ebola virus infection.

Drug NameBlock Ebola VLP entryCytotoxicitySelectivityApproved indicationMOA
IC50(µM)IC90(µM)Max. Inh. (%)IC50 (µM)Index (fold)
Carfilzomib0.4321.8857>500>1156AnticancerProteasome Inhibitor
Deslanoside0.48511.766250515AntiarrhythmicNa+-K+ pump inhibitor
Cepharanthine1.534.4011288.958Anti-inflammatory/AntineoplasticRelease of neutrophil elastase inhibitor
Clomiphene(Clomifene)1.725.349291.453Female infertilityEstrogen receptor modulator
Oxibendazole1.723.7557>500>291AnthelminticDNA Polymerase Inhibitor
Daunorubicin2.434.4596250103Antimicrobial/anticancerDNA Topoisomerase II inhibitor
Niclosamide2.666.6081>500>188AntihelminticSTAT-3 Inhibitor
Zoloft (sertraline)2.739.087973.227AntidepressantSerotonin reuptake inhibitor
Mefloquine2.7313.09443.216AntimalarialHemozoin formation inhibitor
Tilorone3.4319.0100>500>146AntiviralDNA Polymerase Inhibitor
Bazedoxifene3.432.638943.213Postmenopausal osteoporosisEstrogen receptor modulator
Topotecan3.8510.8107>500>130AnticancerDNA Topoisomerase I Inhibitor
Bosutinib3.8521.310143.211AnticancerBcr-Abl inhibitor
Thioproperazine4.3212.5103>500>116AntipsychoticPostsynaptic receptors modulator
Spiramycin4.3211.792>500>116AntimicrobialProtein synthesis inhibitor
Mibefradil4.327.349643.210AntihypertensiveCalcium channel blocker
Amodiaquine4.4327.3106>500>113AntimalarialHistamine N-methyltransferase inhibitor
Bifemelane4.8518.19925052AntidepressantCholinergic system modulator
Bitolterol6.1122.68525041BronchodilatorBeta-adrenergic receptor agonist
Proglumetacin6.8517.393>500>73Anti-inflammatoryCyclooxygenase-1 inhibitor
Aprindine7.6926.693>500>65AntiarrhythmicNa+-K+ pump inhibitor
Cyclomethycaine7.6919.686>500>65AnestheticNa+-K+ pump inhibitor
Posaconazole7.698.3377>500>65AntifungalMembrane-bound enzyme inhibitor
Alverine Citrate8.6321.890>500>58AntispasmodicParasympathetic nervous system modulator
Azaclorzine9.4337.188>500>53AntianginalBeta-adrenergic receptor agonist
Salmeterol9.6813.090>500>52AntiasthmaBeta-adrenergic receptor agonist
Piperacetazine9.6818.190>500>52AntipsychoticDopamine antagonist
Gefitinib9.6817.993>500>52AnticancerEGFR inhibitor
Imipramine13.752.2102>500>36AntidepressantSerotonin norepinephrine reuptake inhibitor
Chloroquine15.313398>500>32AntimalarialHemozoin formation inhibitor
Nilotinib24.310410050.12AnticancerTyrosine kinase inhibitor
 Abbreviation: EGFR, epidermal growth factor receptor.
 These compounds were previously reported to be active in Ebola virus infection assays or animal models.