The
Delta variant have several mutations to enhance infection, so this variant
becomes dominant in the world, which has rationale in the views of natural
selection rule. In the United Kingdom, 77% of sequenced virus is Delta variant
between June 2 and 9, 2021(2). In Japan and South Korea, it is difficult to
control the infection number including Delta variant even in the case that the
political measure is implemented. Therefore, broad vaccination as early as
possible is needed. However, current vaccine is not specially designed for the
Delta variant, so we need to evaluate the efficacy of vaccine like
neutralization ability in a comparative manner for the other variants.
Timothée Bruel, Etienne Simon-Lorière, Felix A. Rey, Olivier
Schwartz et al. compare the neutralization ability of 2 vaccines (Pfizer,
AstraZeneca) against Alpha, Beta and Delta variants(1). The neutralization
ability against Delta variants is about 3-fold lower than Alpha variants, but
higher than Beta variants having escape mutation E484K in both 2 vaccines(1).
Therefore, we need to re-evaluate epidemiological data against Delta variants.
Jamie Lopez Bernal, Nick Andrews, Charlotte Gower et al evaluate the
vaccine efficacy against Delta variants. According to this data, the vaccine
efficacy (Pfizer, full dose regimen) against Alpha and Delta is about 93.7%,
88.0%, respectively(3). Therefore, some level of association between
neutralization ability and prevention against infection can be confirmed.
To evaluate the burden of medical resources, the epidemiological
data on the vaccine efficacy against moderate-to-severe symptom in Delta
variant needs to be published.
(Reference)
(1)
Delphine Planas, David Veyer, Artem
Baidaliuk, Isabelle Staropoli, Florence Guivel-Benhassine, Maaran Michael
Rajah, Cyril Planchais, Françoise Porrot, Nicolas Robillard, Julien Puech,
Matthieu Prot, Floriane Gallais, Pierre Gantner, Aurélie Velay, Julien Le Guen,
Najibi Kassis-Chikhani, Dhiaeddine Edriss, Laurent Belec, Aymeric Seve, Laura
Courtellemont, Hélène Péré, Laurent Hocqueloux, Samira Fafi-Kremer, Thierry
Prazuck, Hugo Mouquet, Timothée Bruel, Etienne Simon-Lorière, Felix A. Rey
& Olivier Schwartz
Reduced sensitivity of SARS-CoV-2 variant
Delta to antibody neutralization
Nature (2021)
---
Author information
Author notes
These authors contributed equally: Timothée
Bruel, Etienne Simon-Lorière, Felix A. Rey, Olivier Schwartz
Affiliations
Virus & Immunity Unit, Department of
Virology, Institut Pasteur, CNRS UMR 3569, Paris, France
Delphine Planas, Isabelle Staropoli,
Florence Guivel-Benhassine, Maaran Michael Rajah, Françoise Porrot, Timothée
Bruel & Olivier Schwartz
Vaccine Research Institute, Creteil, France
Delphine Planas, Timothée Bruel &
Olivier Schwartz
INSERM, Functional Genomics of Solid Tumors
(FunGeST), Centre de Recherche des Cordeliers, Université de Paris and Sorbonne
Université, Paris, France
David Veyer & Hélène Péré
Hôpital Européen Georges Pompidou,
Laboratoire de Virologie, Service de Microbiologie, Paris, France
David Veyer, Nicolas Robillard, Julien
Puech, Dhiaeddine Edriss & Laurent Belec
G5 Evolutionary genomics of RNA viruses,
Department of Virology, Institut Pasteur, Paris, France
Artem Baidaliuk, Matthieu Prot &
Etienne Simon-Lorière
Université de Paris, Sorbonne Paris Cité,
Paris, France
Maaran Michael Rajah
Laboratory of Humoral Immunology,
Department of Immunology, Institut Pasteur, INSERM U1222, Paris, France
Cyril Planchais & Hugo Mouquet
CHU de Strasbourg, Laboratoire de
Virologie, Strasbourg, France
Floriane Gallais, Pierre Gantner, Aurélie
Velay & Samira Fafi-Kremer
Université de Strasbourg, INSERM, IRM UMR_S
1109, Strasbourg, France
Floriane Gallais, Pierre Gantner, Aurélie
Velay & Samira Fafi-Kremer
Hôpital Européen Georges Pompidou, Service
de Gériatrie, Assistance Publique des Hôpitaux de Paris, Paris, France
Julien Le Guen
Hôpital européen Georges Pompidou, Unité
d’Hygiène Hospitalière, Service de Microbiologie, Assistance Publique-Hôpitaux
de Paris, Paris, 75015, France
Najibi Kassis-Chikhani
CHR d’Orléans, service de maladies
infectieuses, Orléans, France
Aymeric Seve, Laura Courtellemont, Laurent
Hocqueloux & Thierry Prazuck
Structural Virology Unit, Department of
Virology, Institut Pasteur, CNRS UMR 3569, Paris, France
Felix A. Rey
(2)
Public Health England. Variants
distribution of cases.
https://www.gov.uk/government/publications/covid-19-variants-genomically-confirmed-case-numbers/variants-distribution-of-case-data-11-june-2021
(2021).
(3)
Jamie Lopez Bernal, F.F.P.H., Ph.D., Nick
Andrews, Ph.D., Charlotte Gower, D.Phil., Eileen Gallagher, Ph.D., Ruth
Simmons, Ph.D., Simon Thelwall, Ph.D., Julia Stowe, Ph.D., Elise Tessier,
M.Sc., Natalie Groves, M.Sc., Gavin Dabrera, M.B., B.S., F.F.P.H., Richard
Myers, Ph.D., Colin N.J. Campbell, M.P.H., F.F.P.H., Gayatri Amirthalingam,
M.F.P.H., Matt Edmunds, M.Sc., Maria Zambon, Ph.D., F.R.C.Path., Kevin E.
Brown, M.R.C.P., F.R.C.Path., Susan Hopkins, F.R.C.P., F.F.P.H., Meera Chand,
M.R.C.P., F.R.C.Path., and Mary Ramsay, M.B., B.S., F.F.P.H.
Effectiveness of Covid-19 Vaccines against
the B.1.617.2 (Delta) Variant
The New England Journal of Medicine July
21, 2021
---
Author Affiliations
From Public Health England (J.L.B., N.A.,
C.G., E.G., R.S., S.T., J.S., E.T., N.G., G.D., R.M., C.N.J.C., G.A., M.E.,
M.Z., K.E.B., S.H., M.C., M.R.), the National Institute of Health Research
(NIHR) Health Protection Research Unit in Vaccines and Immunisation, London
School of Hygiene and Tropical Medicine (J.L.B., N.A., C.N.J.C., G.A., K.E.B.,
M.R.), the NIHR Health Protection Research Unit in Respiratory Infections,
Imperial College London (J.L.B., M.Z.), and Guy’s and St. Thomas’ Hospital NHS
Trust (M.C.), London, and Healthcare Associated Infections and Antimicrobial
Resistance, University of Oxford, Oxford (S.H.) — all in the United Kingdom.
//概要//---
脊髄性筋萎縮症は脊髄と脊髄上部にある脳幹の運動系の神経細胞のSMNタンパク質量が
低下する疾患です。このたんぱく質の不足によって神経細胞のmRNAの機能に関わる
スプライシングの異常に関連し、運動系神経細胞死につながると考えられています。
その中でⅠ型は重症型、急性で発症が生後6か月迄とされています。
発症後は基礎的な運動に関わる体幹を動かすことも難しくなります。
治療が行われない場合においては2年を超えて生存する事が難しいとされています(2-4)。
Ⅰ型脊髄性筋萎縮症に対して
現状では3つの薬物治療がFDAによって承認されています
そのうちの以下、２つについては一定の効果が確認されています(5,6)。
1: Nusinersen,
SMN2-targeting antisense oligonucleotide,
2: Onasemnogene abeparvovec-xioi、
An intravenously administered
adeno-associated virus vector–based gene-replacement therapy,
いずれも異常が生じているSMN1遺伝子に働きかける遺伝子治療ですが、
運動ニューロンは細胞分裂しないために
一旦、細胞内に遺伝子が導入されるとその効果は持続性を持つと考えられています。
2020年10月5日のロシュ、中外製薬のプレスリリースによると
Ⅰ型脊髄性筋萎縮症の乳児を対象にリスジプラムを評価したところ
17/22名において2年間、継続して運動機能が改善している事を示しました。
88%の乳児が生存し、人工呼吸器の永続的な使用を必要としないことが示されました。
このリスジプラムは薬物治療のうち上述した2つに続き、3つ目の薬剤にあたります。
経口投与の薬剤です。
B.T. Darraら医療研究グループによって行われた非盲検研究の結果(1)では
1か月から7か月の乳児に対して治療を開始して
治療後12か月の時点での運動評価をしたところ、
5秒以上支援なしで座る事が出来た乳児は29%
この運動機能は運動機能スケールスコア(CHOP-INTEND)と関連性があり
1名を除くほぼすべての子供において運動機能スケールの向上が見られています。
人工呼吸器が必要のない治療後12カ月時点の生存率は85%となっています。
しかしながら、重篤な副作用は59%の子供が経験しており
副作用として多いのが上部呼吸器感染症68％となっています。
続いて、肺炎、発熱が39%です。
従って、(風邪)コロナウィルスやインフルエンザのような
呼吸器に関わる感染症のリスクが高まると考えられます。
基本的にこのような副作用は免疫機能と関連があると考えられますが、
これらの乳児に対する授乳の状況はどうであったか？
この情報は副作用において重要な可能性があります。
なぜなら、ウィルスに対してデコイ機能がある
多様なオリゴ糖が母乳の中に含まれているからです。
また、薬理と免疫機能の関連についても調査が必要です。
しかしながら、アデノウィルスによる薬物
Onasemnogene abeparvovec-xioiにおいても
同じように気管支のウィルス性炎症の副作用が報告されています(6)。
薬物そのものが血液中の免疫細胞に働きかけるのか
授乳の有無の影響なのか
神経系の命令を介した異常なのか
元々呼吸器系の運動機能が低下している事が原因なのか
それらの複合的要因なのかという疑問があります。
一方、脊髄性筋萎縮症のSMNタンパク質の不足による脾臓、リンパ節の重篤な異常がマウスのケースで確認されています。従って、有害事象は治療の有無に関係なく生じている可能性があります。
//Background(1)//---
Spinal muscular atrophy is one the most frequent mortality and
gene-related diseases in infant, and 8.5-10.3 of 10,0000 children are affected
with spinal muscular atrophy epidemiologically. The children affected with this
disease can not keep homeostasis of motor neuron due to SMI1 mutation which
results to decrease SMN protein and impair mRNA splicing. As clinical symptom,
respiratory and swallowing function decline and they need to receive feeding
and ventilatory support by 12 months of age(4). Most of untreated infants
cannot survive beyond 2 years(2-4). As spinal muscular atrophy is SMN gene
related disease, gene therapy is the main candidates. Currently, following
three treatment(#1-3) have been approved by FDA against spinal muscular
atrophy.
(#1): Nusinersen- An intrathecally
administered SMN2-targeting antisense oligonucleotide(5)
(#2): Onasemnogene abeparvovec-xioi- An intravenously
administered adeno-associated virus vector-based gene-replacement therapy(6)
(#3): Risdiplam- An orally administered
small molecule drug, which promotes the “Inclusion” of exon7(typically exclusion of exon7 in SMA diseases), by which
SMN2 mRNA level and SMN protein increases(7). In this Letter, I refer to a part
of contents in the open-label study of Risdiplam for the children. This drug is
small molecule, so it could penetrate the blood brain barrier.
Basil
T. Darras, M.D., Riccardo Masson, M.D., Maria Mazurkiewicz-Bełdzińska, M.D.,
Kristy Rose, Ph.D., Hui Xiong, M.D., Edmar Zanoteli, M.D., Giovanni Baranello,
M.D., Ph.D., Claudio Bruno, M.D., Ph.D., Dmitry Vlodavets, M.D., Yi Wang, M.D.,
Ph.D., Muna El-Khairi, Ph.D., Marianne Gerber, Ph.D., Ksenija Gorni, M.D.,
Ph.D., Omar Khwaja, M.D., Ph.D., Heidemarie Kletzl, Ph.D., Renata S. Scalco,
M.D., Ph.D., Paulo Fontoura, M.D., Ph.D., and Laurent Servais, M.D., Ph.D. for
the FIREFISH Working Group* conduct an open-label study for the clinical outcome
of risdiplam for the children with Type 1 progressive spinal muscular
atrophy(1). I hope to share a part of contents and my original discussion with
the global important readers.
//Condition(1)//---
*Place: 14 centers in 10 countries
*Eligibility criteria: 5q SMA (Genetic
condition) / Type 1 SMA / Two copies of SMN2
*Age: 1 to 7 months
*Excluded criteria: Invasive ventilation /
awake noninvasive ventilation / tracheostomy / already received treatment other
SMN2-targeting therapies or gene therapy.
-
* Risdiplam Administration condition
A dose 0.2mg per kilogram of body weight
per day for older than 5 months
For infant younger than 5 months, dose is
adjusted (See (1) Study procedures)
//Result(1)//---
Efficacy at Month 12
*Able to sit without support for ≧5 sec : 29%
(Motor function score)
CHOP-INTEND score of ≥40: 56%
This score continues to increase up to 12
months. (See Figure. S3)
*HINES2- motor milestone (Special note)
The
motor function with physical burden like lifting heat (not 85%), legs (not 59%)
is difficult (See Table. S5). Therefore, gradual and continuous gradual
rehabilitation in careful observation by medical staffs is needed.
*Event-free(not permanent ventilation)
survival: 85%
Therefore, we can evaluate the improvement of
motor function through the gene therapy by Risdiplam.
//Adverse event(1)//---
*At least 1 adverse event: 100%
*At least 1 serious adverse event: 59%
(Most common adverse events)
*Upper respiratory tract infection: 68%
*Pneumonia: 39%
*Pyrexia: 39%
(Most common serious adverse events)
*Pneumonia: 32%
From
the 3 major adverse events, immune system of respiratory system may be
disturbed. Whether severe pneumonia is trigged by upper respiratory tract
infection or not needs to be discussed. And breastfeeding highly affects immune
system of infant. Confirming the fact whether breastfeeding is taken or not is
needed. The study about the relation between immune system and Risdiplam
including in vitro may be valuable. There is the report about the relation between
immune dysregulation and spinal muscular atrophy (SMA) in mice model(8). SMN
protein depletion led to severe alteration in the thymus and spleen related to
immune development. Therefore, analysis in immune landscape and histology
and/or function of these organs in the children with SMA is further needed. The
infant is in the crucial developmental stage of the whole bodies including
neurodevelopment and immune system. Therefore, long-term analysis, treatment
and management are a prerequisite for the improvement of quality-of-life of the
patients and the family in line with the impairment of neurodevelopment and
immune development.
//The other clinical perspective//---
The
SMN protein supplementation plus the gene therapy may have room to be considered.
However, this method may trigger immune system excessively. On the other hand,
the amount of SMN protein and the timing(swiftness) can be controlled more
easily than the gene therapy. The amount of SMN protein may need to be analyze
from biomarker. That is because SMN protein may involve not only “In the neuron”, but also the other organ and
immune system “Out of cell”.
//Support(1)//---
Supported by F. Hoffmann–La Roche.
//Special note(1)//---
The study was approved by an ethics
committee at each study site and was conducted in accordance with the
principles of the Declaration of Helsinki and Good Clinical Practice guidelines
described in the protocol.
//Acknowledgement(1)//---
We thank the staff of the Spinal Muscular
Atrophy Foundation and PTC Therapeutics for their collaboration; all the
patients and families who participated in the risdiplam program; the staff of
the clinical study sites around the world for their ongoing partnership and
assistance; and Lindsey Weedon of MediTech Media for medical writing assistance
with an earlier version of the manuscript, funded by F. Hoffmann–La Roche, in
accordance with Good Publication Practice guidelines
(http://www.ismpp.org/gpp3. opens in new tab).
(Reference)
(1)
Basil T. Darras, M.D., Riccardo Masson,
M.D., Maria Mazurkiewicz-Bełdzińska, M.D., Kristy Rose, Ph.D., Hui Xiong, M.D.,
Edmar Zanoteli, M.D., Giovanni Baranello, M.D., Ph.D., Claudio Bruno, M.D.,
Ph.D., Dmitry Vlodavets, M.D., Yi Wang, M.D., Ph.D., Muna El-Khairi, Ph.D.,
Marianne Gerber, Ph.D., Ksenija Gorni, M.D., Ph.D., Omar Khwaja, M.D., Ph.D.,
Heidemarie Kletzl, Ph.D., Renata S. Scalco, M.D., Ph.D., Paulo Fontoura, M.D.,
Ph.D., and Laurent Servais, M.D., Ph.D. for the FIREFISH Working Group*
Risdiplam-Treated Infants with Type 1
Spinal Muscular Atrophy versus Historical Controls
The New England Journal of Medicine 2021;
385:427-435
---
Author Affiliations
From the Department of Neurology, Boston
Children’s Hospital, Harvard Medical School, Boston (B.T.D.); the Developmental
Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan (R.M.,
G.B.), and the Center of Translational and Experimental Myology, IRCCS Istituto
Giannina Gaslini, Genoa (C.B.) — both in Italy; the Department of Developmental
Neurology, Medical University of Gdańsk, Gdańsk, Poland (M.M.-B.); the
Paediatric Gait Analysis Service of New South Wales, the Children’s Hospital at
Westmead and the University of Sydney, Sydney (K.R.); the Department of
Pediatrics, Peking University First Hospital, Beijing (H.X.), and Children’s
Hospital of Fudan University, Shanghai (Y.W.) — both in China; the Department
of Neurology, Faculdade de Medicina, Universidade de São Paulo, São Paulo (E.Z.);
the Dubowitz Neuromuscular Centre, National Institute for Health Research Great
Ormond Street Hospital Biomedical Research Centre, University College London
Great Ormond Street Institute of Child Health, and Great Ormond Street Hospital
for Children NHS Foundation Trust, London (G.B.), Roche Products, Welwyn Garden
City (M.E.-K.), and the Muscular Dystrophy UK Oxford Neuromuscular Centre, the
Department of Paediatrics, University of Oxford, Oxford (L.S.) — all in the
United Kingdom; Russian Children Neuromuscular Center, Veltischev Clinical
Pediatric Research Institute, Pirogov Russian National Research Medical
University, Moscow (D.V.); Pharma Development, Safety (M.G.), Product
Development Medical Affairs — Neuroscience and Rare Disease (K.G., P.F.), and
Pharma Development Neurology (R.S.S.), F. Hoffmann–La Roche, and Roche
Pharmaceutical Research and Early Development, Roche Innovation Center Basel
(O.K., H.K.) — both in Basel, Switzerland; the Division of Child Neurology,
Centre de Références des Maladies Neuromusculaires, the Department of
Pediatrics, University Hospital Liege, University of Liege, Liege, Belgium
(L.S.); and I-Motion, Institut de Myologie, Assistance Publique Hôpitaux de
Paris, Hôpital Armand Trousseau, Paris (L.S.).
(2)
Mercuri E, Bertini E, Iannaccone ST.
Childhood spinal muscular atrophy:
controversies and challenges.
Lancet Neurol 2012; 11: 443-52.
(3)
Munsat TL, Davies KE.
International SMA consortium
meeting
(26-28
June 1992, Bonn, Germany). Neuromuscul Disord 1992; 2: 423-8.
(4)
Finkel RS, McDermott MP, Kaufmann P, et al.
Observational study of spinal muscular
atrophy type I and implications for clinical trials.
Neurology 2014; 83: 810-7.
(5)
Finkel RS, Mercuri E, Darras BT, et al.
Nusinersen versus sham control in infantile-onset
spinal muscular atrophy.
N Engl J Med 2017; 377: 1723-32.
(6)
Mendell JR, Al-Zaidy S, Shell R, et al.
Single-dose gene-replacement therapy for
spinal muscular atrophy.
N Engl J Med 2017; 377: 1713-22.
(7)
Ratni H, Ebeling M, Baird J, et al.
Discovery of risdiplam, a selective
survival of motor neuron-2 (SMN2) gene splicing modifier for the treatment of
spinal muscular atrophy (SMA).
J Med Chem 2018; 61: 6501-17.
(8)
Marc-Olivier Deguise, Yves De Repentigny,
Emily McFall, Nicole Auclair, Subash Sad, Rashmi Kothary
Immune dysregulation may contribute to
disease pathogenesis in spinal muscular atrophy mice
Human Molecular Genetics, Volume 26, Issue
4, 15 February 2017, Pages 801–819
//Background//---
SARS-CoV-2
pandemic is no end even over 1.5 years after the first confirmation. The
infection number in the world increases from early July 2021 again. SARS-CoV-2
repeats mutation and elevates infectivity significantly more than wild type
including Alpha and Delta variants. On the other hand, the vaccination rate of
at lease one dose is about 27.2% as of 24/July, 2021. Herd immunity requires
70-80% vaccination rate. Therefore, vaccine for over 2 times dose plus current
dose is needed mainly for the Low-Middle income countries. There are more than
20 kinds of vaccine in the world. However, the formal physiological,
epidemiological, medical data are not sufficient. Furthermore, demand for
vaccine significantly surpasses supply. To end the pandemic and recover
society, equal vaccine supply and vaccination as early as possible are
important. To this end, we need to build production capacity in the world.
Sputnik
V (which is an adenovirus viral vector vaccine for COVID-19 developed by the
Gamaleya Research Institute of Epidemiology and Microbiology in Russia) is one
of the important vaccines for equal distribution. On 2 February 2021, an
interim analysis from trial indicated 91.6% efficacy without unusual side
effect(2).
Satoshi
Ikegame, Mohammed N. A. Siddiquey, Chuan-Tien Hung et al. analyze the
neutralization ability of Sputnik V for B.1.1.7 and B.1.351 variants(1). I hope
to share a part of the contents with the global important readers.
//Result(1)//---
*Vaccine recipients cohort (n=12) in
Argentina, two dose regimen
Neutralization ability: Geometric mean
titer
B.1.1.7 / Wild Type / B.1.351 / E484K:
87.1 / 49.4 / 7.9 / 17.0
//Discussion//---
Sputnik
V is an adenovirus viral vaccine similar to ChAdOx1 nCoV-19 (Astrazeneca in
U.K.) or Ad26.CoV2.S. (Janssen in Belgium). ChAdOx1 nCoV-19 vaccine has not
confirmed the positive outcomes against mild-moderate case(3). However,
Ad26.CoV2.S. has confirmed a vaccine efficacy of 57% against moderate-to-severe
case, 89% against severe case(4). Epidemiological data (infection, mild,
moderate, severe symptoms) of Sputnik V against current variants including
Delta variant and the other variant especially with immune escape mutation like
E484K is highly demanded.
//Contributions(1)//---
S.I., C.P., J.P.K., and B.H.L. conceived of
and supervised the study. C.P., A.E.V., and A.E. supervised, collected,
analyzed, and provided materials relevant to this study. S.I. developed the
rcVSV-CoV-2 S reverse genetics system. S.I., M.N.A.S., C-T.H., G.H., S.K., and
H.-P.C. were involved in the generation of S mutant viruses. S.I, L.B., S.K.,
M.N.A.S., C.S.S., and K.Y.O. conducted neutralization assays. S.I. and C.-T.H.
developed the Sendai virus protein expressing system and purified RBD-Fc
protein. S.I. and B.H.L. analyzed the data. S.I., B.H.L., and J.P.K. wrote the
paper with input from C.P. and all co-authors.
//Ethics declarations(1)//---
Competing interests
B.L., C.S., and K.Y.O. are named inventors
on a patent filed by the Icahn School of Medicine, which includes the
293T-ACE2-TMPRSS2 (F8-2) cells used for the virus neutralization assay. J.P.K.
is a consultant for BioNTech (advisory panel on coronavirus variants). The
remaining authors declare no competing interests.
//Peer review information(1)//---
Nature Communications thanks Andreas Radbruch
and the other anonymous reviewer(s) for their contribution to the peer review
of this work. Peer reviewer reports are available.
(Reference)
(1)
Satoshi Ikegame, Mohammed N. A. Siddiquey,
Chuan-Tien Hung, Griffin Haas, Luca Brambilla, Kasopefoluwa Y. Oguntuyo,
Shreyas Kowdle, Hsin-Ping Chiu, Christian S. Stevens, Ariel Esteban Vilardo,
Alexis Edelstein, Claudia Perandones, Jeremy P. Kamil & Benhur Lee
Neutralizing activity of Sputnik V vaccine sera
against SARS-CoV-2 variants
Nature Communications volume 12, Article
number: 4598 (2021)
---
Author information
Author notes
These authors contributed equally: Mohammed
N. A. Siddiquey, Chuan-Tien Hung.
These authors jointly supervised this work:
Claudia Perandones, Jeremy P. Kamil, Benhur Lee.
Affiliations
Department of Microbiology at the Icahn
School of Medicine at Mount Sinai, New York, NY, USA
Satoshi Ikegame, Chuan-Tien Hung, Griffin
Haas, Luca Brambilla, Kasopefoluwa Y. Oguntuyo, Shreyas Kowdle, Hsin-Ping Chiu,
Christian S. Stevens & Benhur Lee
Department of Microbiology and Immunology,
Louisiana State University Health Shreveport, Shreveport, LA, USA
Mohammed N. A. Siddiquey & Jeremy P.
Kamil
National Administration of Laboratories and
Health Institutes of Argentina (ANLIS) Dr. Carlos G. Malbrán, Buenos Aires,
Argentina
Ariel Esteban Vilardo, Alexis Edelstein
& Claudia Perandones
(2)
LDenis Y Logunov, DSc Inna V Dolzhikova, PhD *Dmitry V
Shcheblyakov, PhD Amir I Tukhvatulin, PhD Olga V Zubkova, PhDAlina S
Dzharullaeva, MSc Anna V Kovyrshina, MSc Nadezhda L Lubenets, MSc Daria M
Grousova, MSc Alina S Erokhova, MSc Andrei G Botikov, MScFatima M Izhaeva, MSc
Olga Popova, MSc Tatiana A Ozharovskaya, MSc Ilias B Esmagambetov, PhD Irina A
Favorskaya, PhD Denis I Zrelkin, MSc Daria V Voronina, MSc Dmitry N
Shcherbinin, PhD Alexander S Semikhin, PhD Yana V Simakova, MSc Elizaveta A
Tokarskaya, PhD Daria A Egorova, PhD Maksim M Shmarov, DSc Natalia A Nikitenko,
PhD Vladimir A Gushchin, PhD Elena A Smolyarchuk, PhD Sergey K Zyryanov, DSc
Sergei V Borisevich, DSc Prof Boris S Naroditsky, DSc Prof Alexander L
Gintsburg, DSc
Safety and efficacy of an rAd26 and rAd5
vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of
a randomised controlled phase 3 trial in Russia.
The Lancet. 397 (10275): 671–681.
---
Health of the Russian Federation (Sechenov
University), Moscow, Russia (E A Smolyarchuk PhD, Prof A L Gintsburg);
Peoples’Friendship University of Russia (RUDN University), Moscow, Russia (S K Zyryanov DSc); 48 Central Research Institute of the
Ministry of Defence of the Russian Federation, Moscow,
Russia (S V Borisevich DSc)
(3)
Shabir A. Madhi, Ph.D., Vicky Baillie,
Ph.D., Clare L. Cutland, Ph.D., Merryn Voysey, D.Phil., Anthonet L. Koen, M.B.,
B.Ch., Lee Fairlie, F.C.Paeds., Sherman D. Padayachee, M.B., Ch.B., Keertan
Dheda, Ph.D., Shaun L. Barnabas, Ph.D., Qasim E. Bhorat, M.Sc., Carmen Briner,
M.B., B.Ch., Gaurav Kwatra, Ph.D., Khatija Ahmed, F.C.Path. (Micro), Parvinder
Aley, D.Phil., Sutika Bhikha, M.B., B.Ch., Jinal N. Bhiman, Ph.D., As’ad E.
Bhorat, F.R.A.C.G.P., Jeanine du Plessis, B.Sc., Aliasgar Esmail, M.D., Marisa
Groenewald, M.B., B.Ch., Elizea Horne, M.B., B.Ch., Shi-Hsia Hwa, M.Sc., Aylin
Jose, M.B., B.Ch., Teresa Lambe, Ph.D., Matt Laubscher, M.Sc., Mookho
Malahleha, M.B., Ch.B., Masebole Masenya, M.B., Ch.B., Mduduzi Masilela, M.B.,
Ch.B., Shakeel McKenzie, B.Sc., Kgaogelo Molapo, Nat.Dip.O.H.S., Andrew
Moultrie, B.Sc., Suzette Oelofse, M.B., Ch.B., Faeezah Patel, M.B., B.Ch.,
Sureshnee Pillay, B.Sc., Sarah Rhead, M.B., Ch.B., Hylton Rodel, B.Sc., Lindie
Rossouw, M.B., B.Ch., Carol Taoushanis, B.Pharm., Houriiyah Tegally, M.Sc.,
Asha Thombrayil, M.B., B.Ch., Samuel van Eck, R.N., Constantinos K. Wibmer,
Ph.D., Nicholas M. Durham, Ph.D., Elizabeth J. Kelly, Ph.D., Tonya L.
Villafana, Ph.D., Sarah Gilbert, Ph.D., Andrew J. Pollard, F.Med.Sci., Tulio de
Oliveira, Ph.D., Penny L. Moore, Ph.D., Alex Sigal, Ph.D., and Alane Izu, Ph.D.
for the NGS-SA Group, and the Wits-VIDA COVID Group*
Efficacy of the ChAdOx1 nCoV-19 Covid-19
Vaccine against the B.1.351 Variant
The New England Journal of Medicine 2021;
384:1885-1898
---
Author Affiliations
From the South African Medical Research
Council Vaccines and Infectious Diseases Analytics Research Unit (S.A.M., V.B.,
A.L.K., G.K., S.B., J.P., A.J., M.L., S.M., A.M., C.T., A.T., A.I.), African
Leadership in Vaccinology Expertise (C.L.C.), Wits Reproductive Health and HIV
Institute (L.F., E.H., M. Masenya, F.P., S.E.), the Antibody Immunity Research
Unit, School of Pathology (J.N.B., C.K.W., P.L.M.), and the Perinatal HIV
Research Unit (C.B.), Faculty of Health Sciences, and the Department of Science
and Innovation/National Research Foundation South African Research Chair
Initiative in Vaccine Preventable Diseases Unit (S.A.M., V.B., A.L.K., G.K.,
S.B., A.I.), University of the Witwatersrand, and the National Institute for
Communicable Diseases (NICD) of the National Health Laboratory Service (NHLS)
(J.N.B., C.K.W., P.L.M.), Johannesburg, Setshaba Research Centre, Tshwane
(S.D.P., K.A., M. Malahleha, M. Masilela, K.M.), the Division of Pulmonology,
Groote Schuur Hospital and the University of Cape Town (K.D., A.E., S.O.), and
the Family Centre for Research with Ubuntu, Department of Paediatrics,
University of Stellenbosch (S.L.B., M.G., L.R.), Cape Town, Soweto Clinical
Trials Centre, Soweto (Q.E.B., A.E.B.), and the Africa Health Research
Institute (S.-H.H., H.R., A.S.) and the KwaZulu-Natal Research and Innovation
Sequencing Platform (KRISP), University of KwaZulu-Natal (S.P., H.T., T.O.,
A.S.), Durban — all in South Africa; the Oxford Vaccine Group, Department of
Paediatrics (M.V., P.A., S.R., A.J.P.), and Jenner Institute, Nuffield
Department of Medicine (T.L., S.G.), University of Oxford, Oxford, the Faculty
of Infectious and Tropical Diseases, Department of Immunology and Infection,
London School of Hygiene and Tropical Medicine, London (K.D., A.E.), Division
of Infection and Immunity, University College London, London (K.D.), and
AstraZeneca Biopharmaceuticals, Cambridge (N.M.D., E.J.K., T.L.V.) — all in the
United Kingdom; and Max Planck Institute for Infection Biology, Berlin
(S.-H.H., H.R.).
(4)
Johnson & Johnson. Johnson &
Johnson COVID-19 vaccine authorized by U.S. FDA for emergency use — first
single-shot vaccine in fight against global pandemic. February 27, 2021
(https://www.jnj.com/johnson-johnson-announces-single-shot-janssen-covid-19-vaccine-candidate-met-primary-endpoints-in-interim-analysis-of-its-phase-3-ensemble-trial.
opens in new tab).
//Background//---
Hypoxic ischemic encephalopathy emerges due to
not enough oxygen or blood flow, which may develop during pregnancy, delivery
or in the postnatal period. In only mild or moderate case, some children will
experience no health issues, but in severe case, some children have permanent
disability including developmental delay, cerebral palsy, epilepsy or cognitive
impairment. However, mild hypoxic ischemic encephalopathy may be associated
with adverse cognitive and motor outcome(2). Furthermore, negative health
effect is also induced in the other organ including the heart, liver, kidneys
and bowels by oxygen deficient. The cause of hypoxic ischemic encephalopathy is
following(*).
*Problems with blood flow to the placenta
*Preeclampsia
*Maternal diabetes with vascular disease
*Congenital fatal infection
*Drug or alcohol abuse
*Severe fetal anemia
*Heart disease
*Lung malformations
*Umbilical cord problems
*Abruption of the placenta or rupture of
the uterus
*Excessive bleeding from the placenta
*Abnormal fetal position, such as the
breech position
*Prolonged late stages of labor
*Very low blood pressure in the mother
The
standard care for hypoxic ischemic encephalopathy in high-income countries is
therapeutic hypothermia(3-6). However, long-term health impairment after
treatment still remain open issue(7). Combination therapy of therapeutic hypothermia
and (non) pharmacological intervention is under progression. Current cooling
protocols for 72h are reasonably optimal(8).
Mark
Adams, Barbara Brotschi, André Birkenmaier, Katharina Schwendener, Verena
Rathke, Michael Kleber, Cornelia Hagmann & Swiss National Asphyxia and
Cooling Register Group present a Swiss unit-to-unit comparison of theraputic
hypothermia outcome for the children with hypoxia ischemia encephalopathy based
on internationally agreed standardized procedures(1). I hope to share a part of
these contents and general explanation with the global important readers.
//Therapeutic hypothermia//---
Hypothermia decreases spontaneous repolarization of cardiac myocytes
and prolongs duration of action potential and impulse conduction. The
polarization between neurons (cell) is related to cell communication.
Therefore, heart function could improve by therapeutic hypothermia. Actually, J
waves, which is most classic electrocardiographic abnormality, are rarely seen
in mild (32-34℃) hypothermia(9,10). Therefore, hypoxia
could be alleviated through improved heart function by therapeutic hypothermia.
In addition, hypothermia decrease cell metabolic rate, so demand of oxygen is
modified, and has tissue-specific effect such as decreasing excitotoxicity,
limiting inflammation, preventing ATP deletion, reducing free radical
production, and intracellular calcium overload to avoid apoptosis(11). Hence,
neuron and glia cell in the brain of the neonate could be protected by
therapeutic hypothermia.
//Condition(1)//---
Participants: 570 neonates with
hypoxic-ischemic encephalopathy (HIE)
Periode: 2011 to 2018
Place: 10 Swiss units
Based on the standardized Swiss protocol
(SSP) for treatment of HIE with TH
//Short term outcome(1)//---
*Unit 1~10 Total
Time to reach target temperature: 4.1h
Temperature on admission: 34.9℃
Over or undercooling: 29%
Passive cooling: 30%
Hypotension: 67%
Seizures: 36%
Coagulopathy: 40%
Infection: 7%
Persistent pulmonary hypertension of the
newborn: 18%
Died during primary hospitalization: 16%
(84% discharged)
-
//Conclusion(1)//---
The therapeutic
hypothermia for the children with hypoxia ischemia encephalopathy is effective
in short-term, but we have room to improve.
//Special note//---
Timing of hypothermia treatment for the child
with hypoxia ischemic encephalopathy is important. It is shown that this
treatment before 3h of age is better outcome than that after 3h of age(12).
Therefore, we need to implement therapeutic hypothermia immediately after the
birth, so time to reach target temperature may be important. In Mark Adams et
al study, reaching time is about 4.1h. The set cooling temperature was
effective at 33.5℃ in some clinical studies(8,13).
Therefore, the temperature trajectory including over- or under cooling needs to
be refined.
Cranial ultrasound immediately after birth in
the case of brain dysfunction can differentiate several abnormalities including
other cause of neonatal encephalopathy such as hypoplastic corpus callosum,
germinolytic cysts. MRI can provide a reliable guide to progonosis of
neurodevelopmental outcome up to childhood(14-16).
//Contributions(1)//---
All authors were involved in data
collection and study design. MA performed all statistical analyses. MA and CH
analyzed the data, interpreted the results, and wrote the first draft of the
paper and revised the subsequent drafts. All authors critically reviewed the
drafts, read, and approved the final paper.
//Ethics declarations(1)//---
Competing interests
MA receives a salary as network coordinator
for SwissNeoNet, the host of the National Asphyxia and Cooling Register. The
remaining authors have no potential conflicts of interest relevant to this
article to disclose.
//Ethics approval and consent to
participate//---
Data collection, evaluation, and
publication for this study was approved by the Swiss Ethical Committee and the
Swiss Federal Commission for Privacy Protection in Medical Research
(KEK-ZH-Nr2014-0551 and KEK-ZH-Nr2014-0552).
(Reference)
(1)
Mark Adams, Barbara Brotschi, André
Birkenmaier, Katharina Schwendener, Verena Rathke, Michael Kleber, Cornelia
Hagmann & Swiss National Asphyxia and Cooling Register Group
Process variations between Swiss units
treating neonates with hypoxic-ischemic encephalopathy and their effect on
short-term outcome
Journal of Perinatology (2021)
---
Author information
Affiliations
Newborn Research, Department of
Neonatology, University and University Hospital Zurich, Zurich, Switzerland
Mark Adams, Dirk Bassler, Giancarlo
Natalucci & Susanne Böttger
Division of Neonatology and Pediatric
Intensive Care, Children’s University Hospital Zurich, Zurich, Switzerland
Barbara Brotschi, Verena Rathke, Cornelia
Hagmann, Bernhard Frey, Vera Bernet & Beate Grass
Department of Neonatology and Pediatric
Intensive Care, Children’s Hospital St. Gallen, Neonatal and Pediatric
Intensive Care Unit, St. Gallen, Switzerland
André Birkenmaier, Bjarte Rogdo & Irene
Hoigné
Department of Neonatology and Pediatric
Intensive Care, Children’s Hospital, Spitalstrasse, Lucerne, Switzerland
Katharina Schwendener, Martin Stocker,
Thomas M. Berger & Matteo Fontana
Clinic of Neonatology, Cantonal Hospital
Winterthur, Winterthur, Switzerland
Michael Kleber & Lukas Hegi
Department of Neonatology, Children’s
Clinic, Cantonal Hospital Aarau, Aarau, Switzerland
Philipp Meyer & Gabriel Konetzny
Department of Neonatology, University
Children’s Hospital Basel (UKBB), Basel, Switzerland
Sven M. Schulzke, Sven Wellmann & Maya
Hug
Department of Pediatric Intensive Care,
University Hospital Berne, Berne, Switzerland
Tilman Humpl, Bendicht Wagner & Karin
Daetwyler
Department of Neonatology, Children’s
Hospital Chur, Chur, Switzerland
Thomas Riedel, Brigitte Scharrer &
Nicolas Binz
Department of Neonatology, University
Hospital (CHUV), Lausanne, Switzerland
Anita Truttmann & Juliane Schneider
Consortia
Swiss National Asphyxia and Cooling
Register Group
Dirk Bassler, Giancarlo Natalucci, Susanne
Böttger, Bernhard Frey, Vera Bernet, Beate Grass, Bjarte Rogdo, Irene Hoigné,
André Birkenmaier, Martin Stocker, Thomas M. Berger, Matteo Fontana, Katharina
Schwendener, Lukas Hegi, Michael Kleber, Philipp Meyer, Gabriel Konetzny, Sven
M. Schulzke, Sven Wellmann, Maya Hug, Tilman Humpl, Bendicht Wagner, Karin
Daetwyler, Thomas Riedel, Brigitte Scharrer, Nicolas Binz, Anita Truttmann
& Juliane Schneider
(2)
Chalak LF, Nguyen K-A, Prempunpong C, Heyne
R, Thayyil S, Shankaran S, et al.
Prospective research in infants with mild
encephalopathy (PRIME) identified inthe first six hours of life:
neurodevelopmental outcomes at 18-22 months.
PediatrRes. 2018;84:861 –8
(3)
Azzopardi DV, Strohm B, Edwards AD, Dyet L,
Halliday HL, Juszczak E, et al.
Moderate hypothermia to treat perinatal
asphyxial encephalopathy.
N Engl JMed. 2009;361:1349 – 58.
https://doi.org/10.1056/NEJMoa0900854.
(4)
Jacobs SE, Berg M, Hunt R, Tarnow ‐ Mordi WO, Inder TE, Davis PG.
Cooling fornewborns with hypoxic ischaemic
encephalopathy.
Cochrane Database Syst Rev.2013.
https://doi.org/10.1002/14651858.CD003311.pub3.
(5)
Shankaran S, Laptook AR, Ehrenkranz RA,
Tyson JE, McDonald SA, Donovan EF,et al. W
hole-body hypothermia for neonates with
hypoxic-ischemic encephalopathy.
N. Engl J Med. 2005;353:1574 – 84.
(6)
Martinello K, Hart AR, Yap S, Mitra S,
Robertson NJ.
Management and investigation of neonatal
encephalopathy: 2017 update.
Arch Dis Child - Fetal NeonatalEd.
2017;102:F346 – F358.
(7)
Lee AC, Kozuki N, Blencowe H, Vos T,
Bahalim A, Darmstadt GL, et al.
Intrapartum-related neonatal encephalopathy
incidence and impairment at regional and global levels for 2010 with trends
from 1990.
Pediatr Res. 2013;74:50 – 72.
(8)
Wassink G, Davidson JO, Dhillon SK, Zhou K,
Bennet L, Thoresen M, et al. Ther-
apeutic hypothermia in neonatal
hypoxic-ischemic encephalopathy.
Curr NeurolNeurosci Rep. 2019;19:2.
(9)
Lioudmila V. Karnatovskaia, MD, Katja E.
Wartenberg, MD, PhD, and William D. Freeman, MD
Therapeutic Hypothermia for Neuroprotection
Neurohospitalist. 2014 Jul; 4(3): 153–163.
(10)
Polderman KH.
Mechanisms of action, physiological
effects, and complications of hypothermia.
Crit Care Med. 2009;37(7 suppl):S186–S202
(11)
Max Andresen, Jose Tomás Gazmuri, Arnaldo
Marín, Tomas Regueira, and Maximiliano Rovegn
Therapeutic hypothermia for acute brain
injuries
Scand J Trauma Resusc Emerg Med. 2015; 23:
42.
(12)
Thoresen M, Thoresen M, Tooley J, Liu X,
Jary S, Fleming P, et al.
Time is brain:starting therapeutic
hypothermia within three hours after birth improves motoroutcome in asphyxiated
newborns.
Neonatology. 2013;104:228 – 33.
(13)
Shah PS.
Hypothermia: a systematic review and
meta-analysis of clinical trials.
Semin Fetal Neonatal Med. 2010;15:238 – 46.
(14)
Rutherford M, Ramenghi LA, Edwards AD,
Brocklehurst P, Halliday H, Levene M,et al.
Assessment of brain tissue injury after
moderate hypothermia in neonateswith hypoxic – ischaemic encephalopathy: a
nested substudy of a randomisedcontrolled trial.
Lancet Neurol. 2010;9:39 – 45.
(15)
Rutherford M, Ward P, Allsop J,
Malamatentiou C, Counsell S.
Magnetic resonanceimaging in neonatal
encephalopathy.
Early Hum Dev. 2005;81:13 – 25.
(16)
Miller SP, Ramaswamy V, Michelson D,
Barkovich AJ, Holshouser B, Wycliffe N,et al.
Patterns of brain injury in term neonatal
encephalopathy.
J Pediatr.2005;146:453 – 60.
//Background//---
The
cell specific delivery system could deliver nanoparticle in which effective
drug is infused at the target lesion by forming the surface protein (complex)
with high affinity specific to the targeted binding site of the target cell like
cancer or neurological diseases. However, passive releases technique, in which
drug releasing from nanoparticles depends on only intrinsic properties (pH, the
density gradient of chemoattractant, enzymes, blood vessel, retention effect,
binding strength, interstitial fluid pressure, temperature, many barriers
(extracellular matrix, blood brain barrier, blood tumor barrier, endothelial
tissue)), predetermines release profile. Given heterogeneity among patients and
longitudinal environmental change by continuous treatment, passive release
technique may be insufficient to control over the spatiotemporal distribution
of the drug.
To
overcome this challenging drug controlling matter, powerful wireless on-demand
drug delivery technique is suggested(1). This approaches take advantage of
arbitrary extrinsic signals including acoustic waves(2-5), electric field(6,7),
magnetic field(8,9) and electromagnetic radiation(10-12). Seyed M. Mirvakili
& Robert Langer et al. reviews about drug delivery systems exploiting
electric field, magnetic field and electromagnetic radiation. I hope to share a
part of these contents with the global important readers partly in line with
the cell-specific delivery system.
//Electric fields(1)//---
(Conductive polymers)
Conducting polymers are ionically and
electronically conductive, which can change volume through expansion and
contraction triggered by applied electric field. Therefore, this polymer is
used as “Depot (See Fig.1a)”,
this volumetric change enables drug release. For example, poly(dimethyl
aminopropyl acrylamide) (PDMAPAA) loaded with insulin drugs have been
demonstrated arbitrary releasing of drug from this cargo through applied
electric field(13).
There are two ways(#1,2) to apply the electric
field in vivo.
(#1): Sharp needle electrodes inserted into
the dermis layer of skin structure(14).
(#2): Applying metal pads on the surface of
the skin(13).
However, when electrode system is formed in
vivo, the electric double layer is generated where electric potential
exponentially decays. Therefore, at only the place a few nanometers from the
electrodes, the electric potential becomes 36% of strength for the interface of
electrodes. Hence, the field where electric stimulus can be efficiently applied
is limited quite near the electrode.
*The cell specific delivery system
Conductive polymer can be used as “Protected material” of nanoparticles.
Nanoparticles with dense surface materials is susceptible to the surrounding
material including corona formation, by which targeted intrinsic properties
vary in vivo. If these nanoparticles can be protected by the depot and be
released from this depot in a controllable manner, precision of drug-mediated
therapy could be improved.
---
(Electroporation)
Electroporation can be efficiently harnessed
to topical and transdermal drug delivery. In this method, high-voltage pluses
and short pulse width (Typically: >100V, μs~ms) are
applied to the surface of the skin through two electrodes, by which the
electric field emerges in stratum corneum region and this potential enables the
drug delivery (See Fig.1d). This process has been shown to reversibly (able to
recover) disrupt the cell membrane and the lipid bilayer structures in the skin(15,16).
Kinetics of drug including DNA, vaccines, peptides and small-molecule drug is
accordance with electrophoretic migration, which enhances efficiency of
transport by orders of magnitude(17,18). However, the electrical resistance of
the skin near surface (stratum corneum layer) is significantly higher than that
of deeper tissues.
---
(Iontophoresis)
Electroporation can be efficiently harnessed
to topical and transdermal drug delivery. Low-voltage (<10V) galvanostatic
excitation of electrode set on the surface of skin transports drug through
surface to deep region. The main driving force is electrophoresis /
electromigration / electroosmotic flow of surface-charged small-molecule drugs(19).
Previously this method enables only small molecule transport, but currently, delivery
of molecules up to a few kilodalton succeed(20). Concrete application is
following(#).
(#): Lidocaine for local anaesthesia(22),
Tap water for hyperhidrosis treatment(23), Pilocarpine for cystic fibrosis
diagnosis(24), Fentanyl for pain relief(25), Acyclovir for herpes labialis
treatment(21) and Extraction of glucose for glucose monitoring(26), Gemcitabine
to pancreatic cancer tumor(27).
-
*Limitation
1: Slowness of transport (minutes to hours).
2: Small optimal operation windows for
safety and delivery.
*For improvement: the combination with
electroporation, ultrasound(28,29).
---
(Disucussion)
The
additional value of this method for intravenous injection is high positional
arbitrary property (a degree of freedom for the injection site). In other
words, electroporation and iontophoresis enable topical and transdermal drug
delivery for all sites of body surface. Therefore, we can infuse the drug from
the site close to the target lesion.
//Magnetic fields//---
*Advantage
This can make drug deeply penetrate the
tissue with more minimal interaction with the ion than the driving force by the
electronic field.
-
*Typical operation condition
1: Low-frequency magnetic fields: <20kHz
2: High-frequency magnetic fields:
>100kHz
---
(1: Low-frequency magnetic fields)
*Method: Magnetic force is generated by
magnets or electromagnets.
*Mechanically deformation of soft scaffolds
by application to release the drug(30,31).
*Engineered liposome including magnetic
nanoparticles can be harnessed(32).
-
*For transdermal drug delivery: A magnet
(<450mT) is set at the skin’s surface. This makes diamagnetic hydrophilic
drug drive through skin structure. The net charge (+-) of the drug molecule
does not affect the delivery efficiency through skin.
-
*Limitation: Heavy, expensive coil, low
portability, resulting administration in only certain facility.
---
(2: High-frequency magnetic fields)
*Magnetic-field oscillation can generate
heat in metal and magnetic particles used as drug (carrier). This heating
process is due to a Joule heating effect by eddy current. Especially for
single-domain magnetic nanoparticles, Brownian / Neel fluctuation are dominant
for heat generation(33). When heated, the structure is re-arranged, resulting
the diffusion length of drug increase.
-
**Application example:
1: Drug delivery:
*Micro/nano hollow capsules including
liposomes(34-36).
*Polymer based solid particles(37-39)
*Thermal triggering of lower critical
solution temperature (LCST) hydrogels including
poly(N-isopropylacrylamide)(pNIPAM) which is networks of crosslinked long
polymer chains to release drug after heating by magnetic signal(40)(See Fig.2e)
(#)The cell-specific delivery system
LCST
hydrogel can be used as “Protector” of the nanoparticle carriers against environmental dust (corona
formation) in vivo. On-demand release is possible by magnetic signal or the
other thermogenic signals.
*The drug reservoir with the partly door
made of the material with magneto-thermal effect. This door can open
arbitrarily to release drug through magnetic field(41,42)(See Fig.2g).
2: Hyperthermia for tumor ablation(43-46).
---
(Limitation)
*No direct measure to detect temperature in
vivo.
*Precise control system is needed for
optimal operation.
*Necrosis and hypothermic shock in healthy
tissues
*Drug (Cargo) damage
//Electromagnetic radiation//---
(Radio waves)
*Wavelength: 10,000km to 1mm
*Proposed system: Microchips generating
radio waves with on-chip drug reservoir, which can be controlled by transmitter
and microcontroller. However, silicon-based pharmacy-on-a-chip is not
biodegradable, so require removal after the end cycle (full drug release). This
system is costly and uncomfortable for patients.
---
(Infrared)
*Wavelength: 700nm to 1mm.
*Light penetration in skin tissue is
maximum (~4-5 mm) around 870nm (See Fig.5)(47). Therefore, optical signal is
made function down to the deep tissue including hypodermis where blood vessels
exist.
*System: Heat generation by surface plasmon
resonance for irradiated light could release the drug from nanoparticles in
multiple ways including drug releasing surrounding nanoparticles, volume
change, membrane disruption (See Fig.6a).
*Limitation:
1: Low photon conversion efficiency(48,49)
2: Skin tissue damage(48)
3: High spatiotemporal control is needed.
4: Limited material choice
---
(Visible light)
*Wavelength: 400nm to 700nm
*System: Plasmonic resonant system / Light-responsive
organic moieties including vitamin B12 derivative, Trithiocarbonates / Transition
metal compounds (ruthenium complexes)(50,51).
*Limitation
1: Smaller penetration length
#: Limitation (may) be similar to infrared
light.
---
(Ultraviolet)
*Wavelength: 4nm to 400nm
*This energy level is harmful to human body
and could generate tumor, but low-energy side light and low-intensity condition
is useful in triggering drug release.
*System: Volume change (contraction) by
irradiation of UV-light in following materials(#).
#1: Azobenzenes undergo cis-trans
photoisomerization(52,53).
#2: Spiropyran-based nanoparticles contract
by about 52% (103nm to 49nm) when excited with 365 nm ultraviolet light which
is quite low-energy side in ultraviolet(54).
*Limitation:
1: Tissue damage in DNA level
2: Very small penetration depth (<1mm)
#: Limitation (may) be similar to infrared
light.
---
(X-ray)
*Wavelength: 0.01nm to 10 nm
*Synergetic treatment of standard
radiotherapy and drug carrier stimulation for releasing could be implemented
including tumor site(55).
*Considerable penetration length enable
widely application, but side effect by irradiation of X-ray needs to be
carefully considered.
---
(Gamma-rays)
Wavelength: 0.16pm
*Gamma-rays can be used to sterilize some
nano-carriers including chitosan microparticles, liposomes, niosomes, sphingosomes), with
almost no side-effects(56), before administration, but the side effect for
human body needs to be careful after administration.
//Discussion//---
As
reviewed by Seyed M. Mirvakili & Robert Langer(1), the spatiotemporal
controlling of drug releasing from a nano-carrier by exogenic signals including
electric field, magnetic field, light wave is promising. Furthermore, real time
monitoring and analysis including local temperature are needed. However, such
elaborate system entails cost, footprint problems and we cannot provide
administration anywhere including patient’s home. Therefore, the autonomous
drug releasing system in a specific lesion needs to be included. The
cell-specific delivery system could bind the specific site of the lesion, so
there is certain retention time at the lesion. This partly gives autonomy on
releasing in drug delivery system. Of course, we can exploit cell functions
including endocytosis, pinocytosis. Combination strategy of cell-specific
delivery system and exogenic signal for administration has room to be
considered.
//Ethics declarations(1)//---
Competing interests
S.M.M. declares no competing interests.
//Peer review information(1)//---
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//Background(1)//---
(In
a (small?) part of case where either or both mother or/and baby has the
physiological problem of the circulation system including blood vessels due to
infection, inflammation, autoimmunity, heart dysfunction), stroke could emerge
in the pre-born child “to various degrees”, meaning that tiny infarction don’t involve permanent damage.
However, the prevalence of perinatal stroke is approximately 1 in 1,100 birth
in 2020 estimation(2). Therefore, perinatal stroke is never rare disease. This
congenital cerebral blood dysfunction is associated with permanent morbidity
including cerebral palsy, epilepsy, psychosis, cognitive or/and motor
dysfunction(39). Given that even general nurturing is quite demanding,
nurturing for the children with perinatal stroke imposes the heavy physical,
mental, economical burden to both children and families(3,4). As indicated in
Ref.(1) Fig.2, brain functional development could highly vary through early /
longitudinal / proper medical intervention. Recent improvement of both analysis
method (i.e. Neuroimaging) and therapy may enable the patients and the families
to reduce the disease-related burden and alleviate life-long disability.
Adam
Kirton, Megan J. Metzler, Brandon T. Craig, Alicia Hilderley, Mary Dunbar,
Adrianna Giuffre, James Wrightson, Ephrem Zewdie & Helen L. Carlson review
about prenatal stroke in a multiple perspectives(1). I hope to share a small
part of these contents with the global important readers.
//Classification of perinatal stroke//---
*Timing: From the 20th week of
gestation to 28th day of postnatal life(5)
*(Radiographic) Classification: NAIS, NHS,
CSVT, PVI, APPIS, PPHS (See Fig.1)
1: Neonatal arterial ischaemic stroke
(NAIS)
2: Neonatal haemorrhagic stroke (NHS)
3: Cerebral sinovenous thrombosis (CSVT)
4: Periventricular venous infarction (PVI)
5: Arterial presumed perinatal ischaemic
stroke (APPIS)
6: Presumed perinatal
haemorrhagic stroke (PPHS)
Therefore, Ischaemic type /Thrombosis type
/ Haemorrhagic type exists.
//Clinical hallmarks//---
*Non-specific and seizure with/without
encephalopathy(6)
*Asymmetry of movement, Early hand
preference(7)
*Congenital hemiparesis
---
(Potential adverse outcomes)(See Table 1)
*Sensory(high evidence): Impaired proprioception
(blind motor sense) / Visuospatial dysfunction(Spatial perception) / Impaired
spatial orientation and navigation
*Language(high evidence): speaking,
reading, writing, non-verbal communication
*Neuropsychological(Medium evidence):
Attention, Executive, Intellectual, Cognitive, Learning deficits
*Epilepsy(Medium evidence)
*Mental health of parents(Medium): Maternal
guilt, blame, post traumatic stress, depression, anxiety, human relationship
challenges
→We can try to have the symptom of patients
improve through occupational therapy and cognitive therapy as indicated Fig.8.
However, inter-individual variability for efficacy of medical intervene is
high, so some patients gain no functional benefit(8).
//Neuroimaging(1)//---
(MRI: Gold standard approach)
*Advanced diffusion MRI technique
This
technique allows us to analyze white matter function including motor and
sensory pathway in an independent way (See Fig.4a). The microstructural network
is moderately associated with the clinical function in perinatal stroke(9-13).
In the patients with perinatal stroke, neuro-network efficiency (global
efficiency) is higher than in healthy persons in non-lesions(14). Therefore,
compensatory system (plasticity) functions in non-damage brain regions.
-
*Functional MRI
This
takes measurement of temporal fluctuations in the response dependent of the
blood oxygenation level. This level is surrogate marker of neuronal activity(40).
Therefore, spatiotemporal cerebral activity can be analyzed. In the patients
with perinatal stroke, three regional hallmarks(#) can be confirmed during
paretic limb use.
(#)1: Ipsilesional activation / 2: contralesional
activation / 3: bilateral activation
1: Ipsilesional activation represents the
recruitment of remaining perilesional tissue(16-22).
2: Contralesional activation develops the
non-lesioned hemisphere, and helps ipsilesional control of limb(16-20,23-25).
3: Bilateral activation represents
recruitment of the motor cortex in both hemispheres(16,18,20-22,24-27).
Therefore, the brain activity by the blood
flow like neuro-network (electric signaling) is also activated in a
compensatory way. Therefore, longitudinal rehabilitation (occupational therapy)
is important for compensatory recovery.
---
(MRS imaging)
Magnetic resonance spectroscopy (MRS) can
detect the degree of neurometabolic chemical material like neurotransmitter,
whereby neuron activity and glial health can be analyzed in a spatiotemporal
manner. However, this method is not frequently used for the patients with
prenatal strokes.
//Therapeutic approach(1)//---
As indicated in (1)Fig.2, even if brain
injury emerges before birth, brain function could be improved through optimal
modulation in brain developmental stage due to highly brain plasticity.
Therefore, considering longitudinal and multi-dimensional therapies is
important for the children with congenital stroke.
---
(Non-invasive brain stimulation)
Transcranial magnetic stimulation can improve
activity of functional cortical area via electromagnetic induction(29), which
can safe and painless. This method has a sufficient track record in the
children (over 400 />4 million stimulation). There are no seizures or
serious adverse events(28). This therapy is used to control activity balance of
inter-hemisphere.
---
(Manual therapies)
Motor
rehabilitation for children with cerebral palsy can significantly improve
function. Manual therapy is two method(#1,2)(30-32).
(#1): Contraint-induced movement therapy is
that movement of non-damage limb is made limit by cast, by which movement of
damage lesion is promoted (See Fig.8a-c).
(#2): Bimanual therapy is that both hands
are used at the same time (See Fig. 8d-f).
---
(For family)
The education and empathetic counselling of
family may be the most effective to reduce long-term psychological negative
effect including depression, anxiety and post-traumatic stress disorder(3,33,34).
There are some global organizations such as International Pediatric Stroke
Organization and International Alliance for Pediatric Stroke.
//Future directions(1)//---
*Focused ultrasound can modulate human
brain function with high spatial resolution and access to deep structures is
promising(35), but clinical study for children have not been published yet.
*Community-based therapy where the parents
participate in the actual therapy for their child will be required if
longitudinal and frequent intervention is needed.
*Brain-computer interfaces(36,37) and
Robotics need to be considered for implementation.
*Cell-based therapy have been increasingly
studied as a potential treatment for perinatal brain injury(38). Cell-specific
delivery system or this system combined with magnetic stimulation or ultrasound
can be one of the future therapeutic choices.
//Discussion//---
The
global and long-term care for the patients and the families is required. It may
be important to confirm the improvement trajectory among medical staffs, families
and patient step-by-step. Successful experience is one of neurotrophic factors
not only in healthy persons, but in children with the perinatal stroke.
Rehabilitation may be suffering and challenging. Therefore, elaborate and
compassionate support is needed among medical staffs, families, patient.
//Contributions(1)//---
The authors contributed equally to all
aspects of the article.
//Ethics declarations(1)//---
Competing interests
The authors declare no competing interests.
//Peer review information(1)//---
Nature Reviews Neurology thanks S. Chabrier
(who co-reviewed with M. Chevin), A. Guzetta, and the other, anonymous,
reviewer(s) for their contribution to the peer review of this work.
//Publisher’s note(1)//---
Springer Nature remains neutral with regard
to jurisdictional claims in published maps and institutional affiliations.
(Reference)
(1)
Adam Kirton, Megan J. Metzler, Brandon T.
Craig, Alicia Hilderley, Mary Dunbar, Adrianna Giuffre, James Wrightson, Ephrem
Zewdie & Helen L. Carlson
Perinatal stroke: mapping and modulating
developmental plasticity
Nature Reviews Neurology volume 17,
pages415–432 (2021)
---
Author information
Affiliations
Calgary Pediatric Stroke Program, Alberta
Children’s Hospital, Calgary, AB, Canada
Adam Kirton, Megan J. Metzler, Brandon T.
Craig, Alicia Hilderley, Mary Dunbar, Adrianna Giuffre, James Wrightson, Ephrem
Zewdie & Helen L. Carlson
Hotchkiss Brain Institute, University of
Calgary, Calgary, AB, Canada
Adam Kirton, Brandon T. Craig, Alicia
Hilderley, Mary Dunbar, Adrianna Giuffre, James Wrightson, Ephrem Zewdie &
Helen L. Carlson
Alberta Children’s Hospital Research
Institute (ACHRI), Calgary, AB, Canada
Adam Kirton, Megan J. Metzler, Brandon T.
Craig, Alicia Hilderley, Mary Dunbar, Adrianna Giuffre, James Wrightson, Ephrem
Zewdie & Helen L. Carlson
Department of Pediatrics, University of
Calgary, Calgary, AB, Canada
Adam Kirton, Megan J. Metzler, Brandon T.
Craig, Alicia Hilderley, Mary Dunbar, Adrianna Giuffre, James Wrightson, Ephrem
Zewdie & Helen L. Carlson
Department of Clinical Neurosciences,
University of Calgary, Calgary, AB, Canada
Adam Kirton, Megan J. Metzler & Mary
Dunbar
Department of Radiology, University of
Calgary, Calgary, AB, Canada
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//Background//---
In the United Kingdom, the number of new SARS-CoV-2 infection is
47,599 in 19/July, 2021 according to JHU CSSE COVID-19 Data. In this country,
B.1.617.2 (delta) variant mainly emerged in India in December 2020 has been
largely confirmed due to travel from India and with community infection(2). Probably,
the infection wave from early June, 2021 in U.K may mainly include this
variant.
Jamie
Lopez Bernal, Nick Andrews report the epidemiological data on two vaccine
efficacy against infection in a comparative way of B.1.1.7 (Alpha variant) and
B.1.617.2 (Delta variant)(1). I want to share a part of this important report
with the global readers.
//B.1.617.2 delta variant//---
*Spike protein mutations: T19R, Δ157-158, L452R, T478K, D614G, P681R and D950N 1
*Key antigenic binding domain to ACE2
receptor: 452(L452R), 478(L478).
These mutations could elevate infectivity
to cell besides D614G.
*P681R is at the S1-S2 cleavage site
associated to endocytosis into cell, leading to high infectivity(3).
*Therefore, B.1.617.2 could have high
replication rate through high cell infectivity, so it threatens to rapidly make
community transmission.
//Evaluate Condition(1)//---
*Vaccine: BNT162b2(Pfizer/BioNTech), ChAdOx1
nCoV-19 (AstraZeneca)
*Nation: England
*Collected Data: From October 26, 2020 to
May 16, 2021
*Age: 16 years and older than it
*Total: 19,109 participants
*Alpha variant: 14,873 / Delta variant:
4272 -- PCR positive
*Interval from dose 1 to dose 2: about 55
days and 85 days (See Figure S2)
Therefore, interval is longer than general
protocol (21 days).
*PCR conduction criteria: high temperature,
new continuous cough, loss or change in sense of smell or taste
//Result(1)(See Table 2)//---
Total / PCR-positive / infection rate -- in
this order
(Alpha variant)
*Unvaccinated: 96,371 / 7,313 / 0.076
*BNT162b2 vaccine Dose 1(partly
vaccinated):
8,641 / 450 / 0.052 Efficacy: 47.5%
*BNT162b2 vaccine Dose 2(fully vaccinated):
15,749 / 49 / 0.003 Efficacy: 93.7%
* ChAdOx1 nCoV-19 vaccine Dose 1(partly
vaccinated):
42,829 / 1776 / 0.041 Efficacy: 48.7%
*ChAdOx1 nCoV-19 vaccine Dose 2: (fully
vaccinated)
8,244 / 94 / 0.011 Efficacy: 74.5%
-
(Delta variant)
*Unvaccinated: 96,371 / 4,043 / 0.042
*BNT162b2 vaccine Dose 1(partly
vaccinated):
8,641 / 137 / 0.016 Efficacy: 35.6%
*BNT162b2 vaccine Dose 2(fully vaccinated):
15,749 / 122 / 0.008 Efficacy: 88.0%
* ChAdOx1 nCoV-19 vaccine Dose 1(partly
vaccinated):
42,829 / 1356 / 0.032 Efficacy: 30.0%
*ChAdOx1 nCoV-19 vaccine Dose 2: (fully
vaccinated)
8,244 / 218 / 0.026 Efficacy: 67.0%
//Conclusion(1)//---
*Fully vaccination (2 times dose) is needed
to prevent infection owing to significant improvement vaccine efficacy compared
to unvaccinated and Dose 1 groups.
*BNT162b2 vaccine is relatively higher than
ChAdOx1 nCoV-19 vaccine in prevention in 2 times dose condition.
//Discussion//---
*The data on the admission number to a
hospital with moderate-to-severe symptomatic case is needed for evaluation of
social risk against B.1.617.2 variant. Vaccine have been found to be highly
efficacious against symptomatic disease necessary to admission in clinical
trials(4-6) and epidemiologically(7-11). However, to my knowledge, efficacy
rate against moderate-to-severe symptomatic case exclusively on B.1.617.2
(delta) variant has not been officially published. Therefore, the
epidemiological data against these symptomatic case on this variant is socially
needed.
*Vaccination is epidemiologically
effectives even in current spreading Delta variant, so herd immunity owing to
high vaccination rate, but not hesitancy is socially important. Therefore,
polite communication between medicine, government and citizen based on
scientific data including safety issue (i.e. side effect) is needed to elevate
vaccination rate.
//Support(1)//---
Supported by Public Health England (PHE).
The Covid-19 Genomics U.K. Consortium (COG-UK) is supported by funding from the
Medical Research Council part of U.K. Research and Innovation, the National
Institute of Health Research, and Genome Research, operating as the Wellcome
Sanger Institute.
//Special note on ethics//---
Surveillance of coronavirus disease 2019
(Covid-19) testing and vaccination is undertaken under Regulation 3 of the
Health Service (Control of Patient Information) Regulations 2002 to collect
confidential patient information
(www.legislation.gov.uk/uksi/2002/1438/regulation/3/made. opens in new tab)
under Sections 3(i) (a) to (c), 3(i)(d) (i) and (ii), and 3. The study protocol
was subject to an internal review by the Public Health England Research Ethics
and Governance Group and was found to be fully compliant with all regulatory
requirements. Given that no regulatory issues were identified and that ethics
review is not a requirement for this type of work, it was decided that a full
ethics review would not be necessary.
//Acknowledgement(1)//---
We thank the members of the PHE Covid-19
Data Science Team, the PHE Outbreak Surveillance Team, NHS England, NHS
Digital, and NHS Test and Trace for their roles in developing and managing the
testing for severe acute respiratory coronavirus 2 (SARS-CoV-2), variant
identification and vaccination systems, and data sets, as well as the reporting
NHS vaccinators and the staff of the NHS laboratories, PHE laboratories, and
lighthouse laboratories; the staff of the Wellcome Sanger Institute and other
laboratories that were involved in whole-genome sequencing of samples obtained
from patients with Covid-19; the members of the Joint Committee on Vaccination
and Immunisation and the U.K. Variant Technical Group for advice and feedback
in developing this study; and Dr. Neil Ferguson for advice on the analysis.
(Reference)
(1)
Jamie Lopez Bernal, F.F.P.H., Ph.D., Nick
Andrews, Ph.D., Charlotte Gower, D.Phil., Eileen Gallagher, Ph.D., Ruth
Simmons, Ph.D., Simon Thelwall, Ph.D., Julia Stowe, Ph.D., Elise Tessier,
M.Sc., Natalie Groves, M.Sc., Gavin Dabrera, M.B., B.S., F.F.P.H., Richard
Myers, Ph.D., Colin N.J. Campbell, M.P.H., F.F.P.H., Gayatri Amirthalingam,
M.F.P.H., Matt Edmunds, M.Sc., Maria Zambon, Ph.D., F.R.C.Path., Kevin E.
Brown, M.R.C.P., F.R.C.Path., Susan Hopkins, F.R.C.P., F.F.P.H., Meera Chand,
M.R.C.P., F.R.C.Path., and Mary Ramsay, M.B., B.S., F.F.P.H.
Effectiveness of Covid-19 Vaccines against
the B.1.617.2 (Delta) Variant
The New England Journal of Medicine July
21, 2021
---
Author Affiliations
From Public Health England (J.L.B., N.A.,
C.G., E.G., R.S., S.T., J.S., E.T., N.G., G.D., R.M., C.N.J.C., G.A., M.E.,
M.Z., K.E.B., S.H., M.C., M.R.), the National Institute of Health Research
(NIHR) Health Protection Research Unit in Vaccines and Immunisation, London
School of Hygiene and Tropical Medicine (J.L.B., N.A., C.N.J.C., G.A., K.E.B.,
M.R.), the NIHR Health Protection Research Unit in Respiratory Infections,
Imperial College London (J.L.B., M.Z.), and Guy’s and St. Thomas’ Hospital NHS
Trust (M.C.), London, and Healthcare Associated Infections and Antimicrobial
Resistance, University of Oxford, Oxford (S.H.) — all in the United Kingdom.
(2)
Public Health England. SARS-CoV-2
variants of concern
and variants under investigation in England. Technical
briefing 11. May 13, 2021
(https://assets . publishing . service .
gov . uk/ government/ uploads/
system/ uploads/ attachment_data/ file/
986380/
Variants_of_Concern_VOC_Technical _Briefing_11_England . pdf).
(3)
Johnson BA, Xie X, Kalveram B, et al.
Furin cleavage site is key to SARS-CoV-2
pathogenesis. August 26,
2020
(https://www . biorxiv . org/ content/
10 . 1101/ 2020 . 08 . 26 .
268854v1). preprint.
(4)
Polack FP, Thomas SJ, Kitchin N, et al.
Safety
and efficacy of
the BNT162b2 mRNA Covid-19
vaccine.
N Engl J Med 2020; 383: 2603-15.
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Safety and efficacy of the ChAdOx1 nCoV-19
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controlled trials in Brazil, South Africa, and the UK.
Lancet 2021; 397: 99-111.
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Baden LR, El Sahly HM, Essink B, et al.
Efficacy and
safety of the
mRNA-1273 SARS-CoV-2 vaccine.
N Engl J Med 2021; 384: 403-16.
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Lopez Bernal J, Andrews N, Gower C, et al.
Effectiveness of the Pfizer-BioNTech
and Oxford-AstraZeneca vaccines
on covid-19 related symptoms,
hospital ad-missions, and mortality in older adults in England: test negative
case-control study.
BMJ 2021; 373: n1088.
(8)
Hall
VJ, Foulkes S,
Saei A, et al.
COVID-19 vaccine coverage in health-care
workers in England and effectiveness of BNT162b2 mRNA vaccine against infection
(SIREN): a prospective, multicentre, cohort study.
Lancet 2021; 397: 1725-35.
(9)
Shrotri M, Krutikov M, Palmer T, et al.
Vaccine effectiveness of the first dose of
ChAdOx1 nCoV-19 and BNT162b2 against SARS-CoV-2 infection in residents of long-term
care facilities (VIVALDI study).
March 26, 2021 (https://www . medrxiv .
org/ content/ 10 . 1101/
2021 . 03 . 26 . 21254391v1). preprint.
(10)
Thompson MG, Burgess JL, Naleway AL, et al.
Interim estimates of vaccine effectiveness
of BNT162b2 and mRNA-1273 COVID-19
vaccines in preventing
SARS-CoV-2 infection among
health care personnel, first responders, and other
essential and frontline workers — eight U.S. locations, December
2020–March 2021.
MMWR Morb Mortal Wkly Rep 2021; 70: 495-500.
(11)
Dagan
N, Barda N,
Kepten E, et al.
BNT162b2
mRNA Covid-19 vaccine
in a nationwide
mass vaccination setting.
N Engl J Med 2021; 384: 1412-23.
In
the global SARS-CoV-2 pandemic, economic activity has been severely limited,
whereby cash flow is significantly inactivated. In this economic stagnation, cash
distribution in the global is disturbed, resulting large disparity. The persons
who make economic activity in the terminal field of the society always demand
the healthy cash flow to earn it. Strained economy due to COVID-19 crisis makes
the persons especially in low- and middle- income countries suffer. Therefore,
the credit expansion in the large scale and the equal cash distribution are a
prerequisite in a compensatory way, and the credit expansion has been already
conducted, but this is insufficient globally. At least, the global government
needs to guarantee the fundamental life such as food (nutrition state), safe
drink, cloth, sanitation, house.
Actually, economic stagnation related to
SARS-CoV-2 pandemic threaten to exacerbate maternal and child undernutrition
across low- and middle- income countries (LMICs). However, real-time evaluation
is challenging, but The World Health Organization’s Pulse Survey on Continuity
of Essential Health Services During the COVID-19 Pandemic and UNICEF make many
efforts to figure out the current status.
Economic
disruptions in COVID-19 crisis have resulted in the strained nutritional
status, which is lack of nutrition-rich food such as fruits, vegetables and
animal-source food(6,7), and shift to less expensive food (starchy staples,
cereals, oils and/or non-perishable ultra-processed foods)(3-5). These shifts
may increase the risk of undernutrition, especially micronutrient deficiency.
Social protection programs, including cash and food transfers, school meal,
were disrupted at least early in the pandemic(8), and the (financial) resource
of these social support system may be insufficient currently.
Pre-born child, neonate and children are in highly developmental
stage. The epigenetic alteration due to undernutrition especially in pre-born
child may lead to congenital refractory disease. Furthermore, poor nutrition
also for the young children negatively affects both physical and cognitive
development, such as schooling performance / adult productivity / overweight, obesity
/ impair immune response / possibly the response to vaccination / diet-related
non-communicable diseases after maturation(9-11). Of course, pregnant women and
children cannot earn the money by themselves, so financial support mainly from
the spouse is needed. However, COVID-19 pandemic has resulted in millions of
people losing their sources of income. Therefore, the public support is needed
for the family who loses the job. This support is associated with the
fundamental life, such as nutrition status. As mentioned above, the public
organization needs to provide support especially for the financially
insufficient family with the young children and pregnant woman, which is highly
related to the future health of its young children.
To date, there has been no comprehensive assessment for the healthy
status of socially vulnerable people (young children and pregnant women in low-
and middle- income countries). Saskia Osendarp, Jonathan Kweku Akuoku, Robert
E. Black, Derek Headey, Marie Ruel, Nick Scott, Meera Shekar, Neff Walker,
Augustin Flory, Lawrence Haddad, David Laborde, Angela Stegmuller, Milan Thomas
& Rebecca Heidkamp assess and predict the healthy risk for the socially
vulnerable people in low- and middle- income countries in COVID-19 crisis comprehensively(1).
I hope to share a part of these contents with the global important readers.
//Evaluation condition(1)//---
*Saskia Osendarp et al. evaluate the
negative health effect for mothers and children in the COVID-19 crisis.
*Period: From 2020 to 2022
*Object countries: 118 low- and
middle-income countries
*Object persons: 0-59 months children
(<5 years) / Pregnant women (15-49 years)
*Modelling tools: MIRAGRODEP, the Lives
Saved Tool and Optima Nutrition
*Evaluation points: Child stunting/wasting/mortality,
Maternal anemia/Mother BMI at time of birth
*Three scenario: Pessimistic, Moderate,
Optimistic
The optimistic scenario: A fast V-shaped
economic recovery, with economic activity accelerating quickly from 2021
onwards(1).
The moderate scenario: A second major
infection wave into 2021, resulting in a stop-start W-shaped recovery, but also
high vaccine access and stronger recovery by 2022(1).
The pessimistic scenario: A protracted
U-shaped recovery, with continued economic disruptions in 2021 and most
countries not returning to pre-COVID-19 per-capita income levels by 2022(1).
//Result(1)//---
Additional number in each year
In 2020/ In 2021 / In 2022 / Total in 3
years - in this order
(See Table 1)
-
(Pessimistic scenario)
*Wasted children: 5,780,000 / 5,200,000 /
2,630,000 / 13,620,000
*Stunted children: -- / -- / 3,550,000 /
3,550,000
*Deaths in children: 127,000 / 114,000 /
43,000 / 283,000
*Anemia pregnant women: 2,700,000 /
1,400,000 / 700,000 / 4,800,000
*Mother Low BMI at birth: 1,300,000 /
1,100,000 / 600,000 / 3,000,000
-
(Moderate scenario)
*Wasted children: 5,780,000 / 2,980,000 /
530,000 / 9,300,000
*Stunted children: -- / -- / 2,620,000 /
2,620,000
*Deaths in children: 108,000 / 54,000 /
6,000 / 168,000
*Anemia pregnant women: 1,400,000 / 700,000
/ -- / 2,100,000
*Mother Low BMI at birth: 1,300,000 /
700,000 / 100,000 / 2,100,000
-
(Optimistic scenario)
*Wasted children: 5,780,000 / 310,000 /
350,000 / 6,440,000
*Stunted children: -- / -- / 1,540,000 /
1,540,000
*Deaths in children: 96,000 / 12,000 /
-61,000 / 47,000
*Anemia pregnant women: 100,000 / 500,000 /
-400,000 / 1,000,000
*Mother Low BMI at birth: 1,300,000 / 100,000
/ -100,000 / 1,400,000
//Discussion//---
As
of 20/July, 2021, the global vaccination rate is 13.1% according to our world
in data. In low- and middle- income countries, vaccine distribution and
vaccination are significantly delayed due to logistic complexity, production insufficient
capacity and vaccine hesitation. Given current infection status, actual
situation can be corresponding to moderate ~ pessimistic scenario. At least,
the world economy does not experience V-shape recovery in 2021 which is
optimistic scenario. Therefore, the large number of the young children and
pregnant women in low- and middle- income countries could be negatively
affected in their nutritional status according to Saskia Osendarp et al
prediction(1). Hence, scaled up and sustainable social safety net program
including cash and food transfer in more than 200 countries is needed(12,13).
Fundamentally, the global vaccination needs to proceed as early as possible, if
not, social safety net program cannot efficiently function.
//Contributions(1)//---
J.K.A., R.E.B., D.H., R.H., S.O., M.R.,
N.S., M.S. and N.W. conceptualized and designed the study, performed the
primary analyses and wrote and edited the manuscript. A.F., L.H., D.L., A.S.
and M.T. contributed to conceptualization, analysis and editing of the
manuscript. All authors reviewed and approved the final version of the
manuscript.
//Corresponding author(1)//---
Correspondence to Saskia Osendarp.
//Ethics declarations(1)//---
Competing interests
The authors declare no competing interests.
//Additional information(1)//---
Peer review information Nature Food thanks
Kenji Shibuya, Heather Brown and the other, anonymous, reviewer(s) for their
contribution to the peer review of this work.
//Publisher’s note(1)//---
Springer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
(Reference)
(1)
Saskia Osendarp, Jonathan Kweku Akuoku,
Robert E. Black, Derek Headey, Marie Ruel, Nick Scott, Meera Shekar, Neff
Walker, Augustin Flory, Lawrence Haddad, David Laborde, Angela Stegmuller,
Milan Thomas & Rebecca Heidkamp
The COVID-19 crisis will exacerbate
maternal and child undernutrition and child mortality in low- and middle-income
countries
Nature Food (2021)
---
Author information
Affiliations
Micronutrient Forum, Washington, DC, USA
Saskia Osendarp
World Bank, Washington, DC, USA
Jonathan Kweku Akuoku & Meera Shekar
Johns Hopkins Bloomberg School of Public
Health, Baltimore, MD, USA
Robert E. Black, Neff Walker, Angela
Stegmuller & Rebecca Heidkamp
International Food Policy Research
Institute (IFPRI), Washington, DC, USA
Derek Headey, Marie Ruel & David
Laborde
Burnet Institute, Melbourne, Victoria,
Australia
Nick Scott
Asian Development Bank, Washington, DC, USA
Augustin Flory & Milan Thomas
Global Alliance for Improved Nutrition
(GAIN), Geneva, Switzerland
Lawrence Haddad
(2)
Headey, D. et al.
Impacts of COVID-19 on childhood
malnutrition and nutrition-related mortality.
Lancet 396, 519–521 (2020).
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Kansiime, M. K. et al.
COVID-19 implications on household income
and food security in Kenya and Uganda: findings from a rapid assessment.
World Dev. 137, 105199 (2021).
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Ammar, A. et al.
Effects of COVID-19 home confinement on
eating behaviour and physical activity: results of the ECLB-COVID19
International Online Survey.
Nutrients 12, 1583 (2020).
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COVID-19: A Real-Time Review of Country Measures
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https://openknowledge.worldbank.org/handle/10986/33635
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