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Review

COVID-19 vaccines and autoimmune disorders: A scoping review protocol

  • Two years into the global vaccination campaign, important questions about COVID-19 vaccines and autoimmune disorders have arisen. A growing number of reports have documented associations between vaccination and autoimmunity, and research is needed to elucidate the nature of these linkages as well as the mechanisms and causal directions (i.e., whether persons with no history of autoimmune disorders may experience them upon vaccination or persons with autoimmune disorders may experience exacerbation or new adverse events, autoimmune or not, post-vaccination). This scoping review will follow Arksey and O'Malley's framework, which is enhanced by Levac et al.'s team-based approach, to address the relationship between COVID-19 vaccinations and autoimmune disorders. Moreover, it will explore the evidence informing the consensus of care concerning COVID-19 vaccinations in people experiencing these disorders. Data from refereed articles and preprints will be synthesized through a thematic analysis. A subgroup analysis will compare the findings according to the previous existence of autoimmune disorders, presence of co-morbidities, vaccine type, and other potentially relevant factors. COVID-19 has triggered the largest vaccination campaign in history. Drug safety is critical to properly assess the balance of risks and benefits of any medical intervention. Our investigation should yield information useful to assist in clinical decision-making, policy development, and ethical medical practices.

    Citation: Claudia Chaufan, Laurie Manwell, Camila Heredia, Jennifer McDonald. COVID-19 vaccines and autoimmune disorders: A scoping review protocol[J]. AIMS Medical Science, 2023, 10(4): 318-328. doi: 10.3934/medsci.2023025

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  • Two years into the global vaccination campaign, important questions about COVID-19 vaccines and autoimmune disorders have arisen. A growing number of reports have documented associations between vaccination and autoimmunity, and research is needed to elucidate the nature of these linkages as well as the mechanisms and causal directions (i.e., whether persons with no history of autoimmune disorders may experience them upon vaccination or persons with autoimmune disorders may experience exacerbation or new adverse events, autoimmune or not, post-vaccination). This scoping review will follow Arksey and O'Malley's framework, which is enhanced by Levac et al.'s team-based approach, to address the relationship between COVID-19 vaccinations and autoimmune disorders. Moreover, it will explore the evidence informing the consensus of care concerning COVID-19 vaccinations in people experiencing these disorders. Data from refereed articles and preprints will be synthesized through a thematic analysis. A subgroup analysis will compare the findings according to the previous existence of autoimmune disorders, presence of co-morbidities, vaccine type, and other potentially relevant factors. COVID-19 has triggered the largest vaccination campaign in history. Drug safety is critical to properly assess the balance of risks and benefits of any medical intervention. Our investigation should yield information useful to assist in clinical decision-making, policy development, and ethical medical practices.



    The main purpose of this note is to provide an alternative construction of nonnegative and nonradially symmetric initial data for some Keller–Segel-type models which will enforce finite or infinite blowup. Consider the following functional:

    F(u,v):=Ω(uloguuv+12|v|2+12v2)dx,

    where ΩR2 is a bounded domain with C2 boundary Ω and a pair of nonnegative smooth functions (u,v). The main result of this note is stated as follows.

    Theorem 1.1. For any M>0 and Λ(4π,) there exists a pair of nonnegative functions (u0,v0)(C(¯Ω))2 satisfying

    {u0L1(Ω)=Λ,F(u0,v0)<M.

    The above functional F(u,v) appears in the study of the minimal Keller–Segel system:

    {ut=Δu(uv)xΩ,t>0,vt=Δvv+uxΩ,t>0,νu=νv=0xΩ,t>0,u(x,0)=u0(x),v(x,0)=v0(x),xΩ, (1.1)

    and also one of the following chemotaxis model featuring a signal-dependent motility function of the negative exponential type:

    {ut=Δ(evu)xΩ,t>0,vt=Δvv+uxΩ,t>0,νu=νv=0xΩ,t>0,u(x,0)=u0(x),v(x,0)=v0(x),xΩ. (1.2)

    Classical positive solutions of (1.1) satisfy the following energy-dissipation identity ([4,9]):

    ddtF(u,v)(t)+Ωu|loguv|2dx+vt2L2(Ω)=0,

    while for the classical solutions to (1.2), there holds ([2]):

    ddtF(u,v)(t)+Ωuev|loguv|2dx+vt2L2(Ω)=0.

    In both cases, the above energy identities will immediately give rise to the a priori upper bound for F(u,v)(t). On the other hand, for any given initial data of small total mass such that u0L1(Ω)<4π, one could derive a lower bound for the energy functional and then the classical solutions of both systems (1.1) and (1.2) exist globally in time and remain bounded uniformly in the two-dimensional setting (see [2,4,7,9]). For large data, unbounded solutions of the above problems could be constructed based on observations of the variational structure of the stationary problem and by taking an advantage of the subtle connection between its associated functional with the energy F. In [5] the authors introduced a transformation problem of the original system (1.1) with the unknowns being the cell density and the relative signal concentration. Then they constructed unbounded solutions for the transformed problem, which in turn implied blowup of the original one.

    In this note we would rather to construct an unbounded solution to the original system (1.1) or (1.2) in a more direct way. To this aim, let us sketch the main idea of the construction of an unbounded solution following [11] (see also [5]). First, the corresponding stationary solutions (us,vs) to (1.1) or (1.2) satisfy the following problem:

    {vsΔvs=ΛΩevsdxevsin Ω,us=ΛΩevsdxevsin Ω,vsν=0on Ω, (1.3)

    for some Λ>0. Denote

    S(Λ):={(us,vs)C2(¯Ω):(us,vs) is a solution to (1.3) }

    for Λ>0. By [5,Lemma 3.5] and [10,Theorem 1], for Λ4πN there exists some C>0 such that

    sup{(us,vs)L(Ω):(us,vs)S(Λ)}C

    and

    F(Λ):=inf{F(us,vs):(us,vs)S(Λ)}C.

    On the other hand, let (u,v) be the classical positive solution to (1.1) or (1.2) in Ω×(0,). If the solution is uniform-in-time bounded, by the compactness method (cf. [13,Lemma 3.1]), there exist a sequence of time {tk}(0,) and a solution (us,vs) to (1.3) with Λ=u0L1(Ω) such that limktk= and that

    limk(u(tk),v(tk))=(us,vs)inC2(¯Ω),

    as well as

    F(us,vs)F(u0,v0).

    Thus taking account of the above discussion, for a pair of nonnegative functions (u0,v0) satisfying

    {u0L1(Ω)=Λ4πN,F(u0,v0)<F(Λ), (1.4)

    the corresponding solution must be unbounded or blow up in finite time.

    Recently in [2], we constructed nonnegative initial data satisfying (1.4) when Λ(8π,) in the radially symmetric case, which differs from those given in [5]. However, it was left open whether our idea for a construction of adequate initial data can be extended to the nonradial symmetric case if Λ(4π,8π). Theorem 1.1 of the present work gives an affirmative answer to this question and as a consequence, we have an alternative proof of the following corollaries ([5]).

    Corollary 1.2. For any Λ(4π,)4πN there exists a nonnegative initial datum (u0,v0) satisfying (1.4) such that the corresponding classical solution of (1.1) satisfies either:

    exists globally in time and lim supt(u(t)L(Ω)+v(t)L(Ω))=;

    blows up in finite time.

    Remark 1.3. Finite time blowup solutions of the corresponding parabolic-elliptic system are constructed if Λ>4π in [8].

    As to the system (1.2), global existence of classical solutions with any nonnegative initial data was guaranteed in [2], which excluded the possibility of finite-time blowup. Hence, we arrive at the following:

    Corollary 1.4. For any Λ(4π,)4πN there exists a nonnegative initial datum (u0,v0) satisfying (1.4) such that the corresponding global classical solution of (1.2) blows up at time infinity.

    In previous works [3,6,12,13], nonnegative initial data with large negative energy were constructed in several modified situations, e.g., the higher dimensional setting, the nonlinear diffusion case, the nonlinear sensitivity case and the indirect signal case. In those works, the initial datum has a concentration at an interior point of Ω. Similarly, in our precedent work [2], we constructed an initial datum which concentrates at the origin based on certain perturbation of the rescaled explicit solutions to the elliptic system

    {ΔV=UxR2,eV=UxR2,R2U=8π,

    provided that the total mass Λ>8π. However, without the radially symmetric requirement and when 4π<Λ<8π, we need to construct an initial datum that concentrates at a boundary point. To this aim, some cut-off and folding-up techniques are introduced. Besides, a lemma of analysis (Lemma 2.2) plays a crucial role in estimating the value of each individual integral in the energy functional and in order to get vanishing estimations of the error terms, the radius of the cut-off function used in our case needs to depend on the rescaled parameter as well, which in contrast was fixed in the radially symmetric case in [2].

    A straightforward calculation leads us to the following lemma.

    Lemma 2.1. For any λ1 and r(0,1), the functions

    uλ(x):=8λ2(1+λ2|x|2)2,vλ(x):=2log1+λ21+λ2|x|2+log8for all xR2,

    satisfy

    R2uλdx=8π,uλ(x)8λ2,vλ(x)>log8>0in Br(0):={xR2||x|<r}.

    Since Ω is C2 class, for any boundary point PΩ there exist some R=RP(0,1) and some C2 function γP:RR such that

    ΩBR(0)={(x1,x2)BR(0)|x2>γP(x1)}

    (cf. [1,Appendix C.1]). Moreover since Ω is a bounded domain, we can find some point P0=(P1,P2)Ω satisfying that there exists R(0,R) such that

    (γP0)(x1)0for all |P1x1|<R. (2.1)

    By translation, we may assume P0=(0,0). Hereafter we fix the above R(0,1) and γ=γP0. In this setting, we have the following lemma:

    Lemma 2.2. Let f:R2R be a radially symmetric, nonnegative and continuous function. For any r(0,R) it follows that

    12Br(0)f(x)dxK(R)(supxBr(0)f(x))r3Br(0)Ωf(x)dx12Br(0)f(x)dx,

    where

    K(R):=max|ξ|Rγ(ξ)>0. (2.2)

    Proof. We first note that for any r(0,R),

    ΩBr(0)={(x1,x2)Br(0)|x2>γ(x1)}.

    Since γ(0)=0 and the assumption (2.1), it follows by Taylor's theorem that for all x1(R,R) we have

    γ(0)x1γ(x1)γ(0)x1+12K(R)x21,

    where K(R):=max|ξ|Rγ(ξ)>0. Thus we can deduce that

    A+ε(ΩBr(0))A,

    where

    A+ε:={(x1,x2)Br(0)|x2>γ(0)x1+12K(R)r2},A:={(x1,x2)Br(0)|x2>γ(0)x1}.

    By denoting

    B+ε:={(x1,x2)Br(0)|γ(0)x1+12K(R)r2x2>γ(0)x1},

    we confirm that

    A+ε=AB+ε.

    Since the radial symmetry of f implies

    Af(x)dx=12Br(0)f(x)dx,

    we have

    12Br(0)f(x)dxB+εf(x)dxΩBr(0)f(x)dx12Br(0)f(x)dx.

    Since

    |B+ε|12K(R)r22r=K(R)r3,

    we have that

    12Br(0)f(x)dx(supxBr(0)f(x))K(R)r3ΩBr(0)f(x)dx12Br(0)f(x)dx,

    which concludes the proof.

    For any 0<η1<η2 we can construct a radially symmetric function ϕη2,η1C(R2) satisfying

    ϕη2,η1(B(0,η1))={1}, 0ϕη2,η11, ϕη2,η1(R2B(0,η2))={0}, xϕη2,η1(x)0.

    For any λ>max{1,(4R)65}, we fix

    r:=λ56,r1:=r2,

    and then 0<r1<r<min{1,R4}. Noting that

    f(λ):=111+(λr1)2=144+λ131 as λ,

    and by the increasing property of f, we can find λ>max{1,(4R)65} such that

    4πf(λ)8K(R)λ12>2π,

    where K(R) is defined in (2.2). Here we confirm that for any λ>λ,

    4πf(λ)8K(R)λ12>2π.

    Now we define the pair

    (u0,v0):=(auλϕr,r1χΩ,avλϕR2,R4χΩ)

    with some a>0. Here we remark that u0 and v0 are nonnegative functions belonging to C(¯Ω).

    Lemma 2.3. Let Λ(4π,). For λ>λ there exists

    a=a(λ)(Λ4π,Λ2π) (2.3)

    such that

    Ωu0dx=Λ. (2.4)

    Proof. Firstly by changing variables, we see that

    B(0,)uλdx=8B(0,λ)dy(1+|y|2)2=8π(λ)20dτ(1+τ)2=8π(111+(λ)2) for >0, (2.5)

    and that

    8π(111+(λr1)2)<Br(0)uλϕr,r1dx<8π(111+(λr)2).

    Here in light of the radial symmetry of uλϕr,r1, we can invoke Lemma 2.2 to have

    4π(111+(λr1)2)K(R)8λ2r3<Ωuλϕr,r1χΩdx<4π(111+(λr)2),

    where we used

    maxxBr(0)uλϕr,r1(x)=8λ2andΩuλϕr,r1χΩdx=Br(0)Ωuλϕr,r1dx.

    By the choice of r>0, we have

    4πf(λ)8K(R)λ12<Ωuλϕr,r1χΩdx.

    Therefore for any λ>λ we find some a=a(λ) satisfying

    Λ4π<a<Λ2π

    and (2.4). We conclude the proof.

    Lemma 2.4. There exists C>0 such that for all λ>λ,

    Ωu0logu0dx8πalogλ+C, (2.6)

    where a=a(λ) is defined in Lemma 2.3.

    Proof. Since slogstlogt+1e for st and u0auλχBr(0)Ω, it follows

    Ωu0logu0dxΩ(auλχBr(0)Ω)log(auλχBr(0)Ω)dx+|Ω|eaΩuλχBr(0)Ωloguλdx+(aloga+e1)Ωuλdx+|Ω|e.

    Since loguλlog(8λ2)=2logλ+log8 and Ωuλ8π, we have

    Ωu0logu0dx2alogλΩuλχBr(0)Ωdx+8π(alog8+aloga+e1)+|Ω|e.

    By Lemma 2.2 we obtain

    ΩuλχBr(0)Ω12Br(0)uλ12R2uλ=4π.

    Therefore

    Ωu0logu0dx8πalogλ+C,

    where we remark that the constant C is independent of a and λ in view of (2.3). We conclude the proof.

    Lemma 2.5. There exists C>0 such that for all λ>λ,

    Ωu0v0dx16πa2logλ64πa2logλ4+λ13K(R)λ12(2log(1+λ2)+log8)C, (2.7)

    where a=a(λ) is defined in Lemma 2.3.

    Proof. Using vλ>0 in B(0,r), u0=0 on B(0,r)c and r1<R4, we see that

    Ωu0v0dxa2B(0,r1)uλvλχBr1(0)Ωdx.

    Since uλvλ is radially symmetric and

    maxxBr1(0)uλvλ(x)=8λ2(2log(1+λ2)+log8),

    we apply Lemma 2.2 and recall r1=21λ56 to deduce that

    Ωu0v0dx12a2B(0,r1)uλvλdxK(R)8λ2(2log(1+λ2)+log8)r31=12a2B(0,r1)uλvλdxK(R)λ12(2log(1+λ2)+log8).

    Since

    vλ(x)>2log1+λ21+λ2|x|2 for xB(0,r1),

    we have that

    12a2B(0,r1)uλvλdx12a2B(0,r1)uλ2log1+λ21+λ2|x|2dx>2a2logλB(0,r1)uλdxa2B(0,r1)uλlog(1+λ2|x|2)dx.

    By (2.5), it follows

    2a2logλB(0,r1)uλdx2a2logλ8π(111+(λr1)2)=16πa2logλ64πa2logλ4+λ13.

    On the other hand, by (2.3) and direct calculations we see

    a2B(0,r1)uλlog(1+λ2|x|2)dx=8a2B(0,r1)λ2log(1+λ2|x|2)(1+λ2|x|2)2dx=16πa2λr10slog(1+s2)(1+s2)2ds<8πa20log(1+ξ)(1+ξ)2dξ<.

    Combining above estimates, we obtain that

    Ωu0v0dx16πa2logλ64πa2logλ4+λ13K(R)λ12(2log(1+λ2)+log8)C

    for λ>λ with some positive constant C, which is independent of a and λ due to (2.3).

    Lemma 2.6. For any ε1>0 there exists C(ε1)>0 such that for all λ>λ,

    12Ω(v20+|v0|2)dx8π(1+ε1)a2logλ+C(ε1), (2.8)

    where a=a(λ) is defined in Lemma 2.3.

    Proof. Since

    1+λ21+λ2|x|21+λ2λ2|x|2(2|x|)2for λ>1,

    we see that for λ>1

    |vλ(x)|4log2|x|+log8  in B1(0).

    Hence it follows from straightforward calculations that there is a positive constant C satisfying

    Ωv20dxa2B1(0)(4log2|x|+log8)2dxC, (2.9)

    where the constant C is independent of a and λ due to (2.3).

    Moreover by Young's inequality, for any ε1>0 there exists C(ε1)>0 such that

    |v0|2=a2|ϕR2,R4vλ+ϕR2,R4vλ|2χBR2(0)Ωa2(1+ε1)ϕ2R2,R4|vλ|2χBR2(0)Ω+C(ε1)a2|ϕR2,R4|2v2λχBR2(0)Ω.

    Since by (2.9) we have some C>0 such that

    a2Ω|ϕR2,R4|2v2λχBR2(0)ΩdxC

    and by the direct calculations, we have

    |vλ(x)|=4λ2|x|1+λ2|x|2,

    and then we infer that

    Ω|v0|2dxa2(1+ε1)Ωϕ2R2,R4|vλ|2χBR2(0)Ωdx+C(ε1)a2Ω|ϕR2,R4|2v2λdx16a2(1+ε1)BR2(0)Ωλ4|x|2(1+λ2|x|2)2dx+C(ε1)

    with some C(ε1)>0. Since λ4|x|2(1+λ2|x|2)2 is radially symmetric, we can invoke Lemma 2.2 to see

    Ω|v0|2dx8a2(1+ε1)BR2(0)λ4|x|2(1+λ2|x|2)2dx+C(ε1),

    thus

    12Ω|v0|2dx4a2(1+ε1)B1(0)λ4|x|2(1+λ2|x|2)2dx+C(ε1)2.

    On the other hand,

    B1(0)λ4|x|2(1+λ2|x|2)2dx=πλ20τ(1+τ)2dτπλ2011+τdτ=πlog(1+λ2).

    Since λ>1, it follows

    log(1+λ2)log(2λ2)=2logλ+log2.

    Hence

    12Ω|v0|2dx4πa2(1+ε1)(2logλ+log2)+C(ε1)2.

    Therefore we conclude

    12Ω|v0|2dx8πa2(1+ε1)logλ+C(ε1),

    where the constant C(ε1) is independent of a and λ due to (2.3).

    Proof of Theorem 1.1. For any Λ(4π,), we have Λ/4π>1. In view of (2.3), we can fix ε1>0 independently of λ such that (1ε1)a1>(1ε1)Λ4π1>0, where a=a(λ) is defined in Lemma 2.3. Then it follows that

    a((1ε1)a1)>Λ4π((1ε1)Λ4π1)>0,for all λ>λ. (2.10)

    Collecting (2.6), (2.7) and (2.8), we infer that there exists some C>0 such that

    F(u0,v0)I1logλ+I2+C,

    where

    I1:=8πa16πa2+8πa2(1+ε1)=8πa((1ε1)a1),I2:=64πa2logλ4+λ13+K(R)λ12(2log(1+λ2)+log8).

    Here (2.10) implies I1<0 for all λ>λ. On the other hand, we note

    limλI2=0.

    Based on the above discussion, for Λ(4π,) and M>0, we can choose some λ>λ such that

    F(u0,v0)<M.

    We conclude the proof.

    The authors thank the anonymous referee's careful reading and useful suggestions. K. Fujie is supported by Japan Society for the Promotion of Science (Grant-in-Aid for Early-Career Scientists; No. 19K14576). J. Jiang is supported by Hubei Provincial Natural Science Foundation under the grant No. 2020CFB602.

    The authors declare no conflict of interest.


    Acknowledgments



    This work has been partially funded by a New Frontiers in Research Fund (NFRF) 2022 Special Call, NFRFR-2022-00305.

    Conflict of interest



    The authors declare no conflicts of interest with respect to the research, authorship, and/or publication of this article. Funders and professional/academic affiliations have played no role in its conception, or decision to conduct the research, or submit it for publication.

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