If a rabies vaccine is given immediately before, during, or after standing twice weekly pheresis, what is the risk of it losing efficacy due to partial or complete elimination prior to its effect on the body?

Comment by InpharmD Researcher

Unfortunately, our literature search was unable to identify any definitive data or guidance regarding administration of rabies immunoglobulin during ongoing therapeutic plasma exchange (TPE). No clinical studies appear to specifically assess this scenario and its impact on vaccine efficacy. However, more broad discussions pertaining to the effects of TPE on vaccines suggest it may substantially reduce circulating immunoglobulins and vaccine-derived antibodies during or within 2 to 4 weeks before plasma exchange and that there may be a compromised vaccine response due to removal of vaccine antigen by TPE. Studies have found up to 79.6% reduction in immunoglobulin G (IgG) during selective plasma exchange performed on three consecutive days, with data suggesting there is subsequent replenishment between treatments. However, it remains unclear if an intramuscular rabies vaccine would be completely or substantially removed before immune priming with TPE.
Background

According to a 2022 review addressing use of immunotherapies in neuroimmunologic diseases, vaccination should ideally be completed before immunotherapy when feasible, and antibody titer monitoring may be considered when responses may be diminished. In cases of plasma exchange, the authors note that vaccine responses have not been systematically studied during exchange sessions. Vaccines administered during plasma exchange or 2 to 4 weeks before sessions may have compromised responses, as vaccine antigens could be removed during the exchange; similarly, passive immunization with immunoglobulin may be ineffective during this period because circulating antibodies are directly removed. Importantly, plasma exchange does not eliminate cellular immune mechanisms, and after completion of treatment, cytokine and immunoglobulin production are expected to normalize within days. Based on these considerations, the authors suggest that vaccination generally does not need to be delayed for more than 1 to 2 weeks after completion of plasma exchange, while acknowledging that studies directly defining vaccine immunogenicity and optimal timing around plasma exchange are lacking. [1]

Mechanistically, membrane therapeutic plasma exchange (TPE) separates plasma from other cellular components of blood through a highly permeable membrane; the removed plasma is discarded, and an equal volume of replacement fluid, typically albumin or fresh frozen plasma, is infused. The procedure is designed to remove large-molecular-weight substances such as immunoglobulins, proteins, immune complexes, and lipoproteins that are not effectively removed by conventional dialysis or hemofiltration. Modern plasma-separation membranes have very high sieving coefficients for plasma proteins, including a sieving coefficient of approximately 1 for immunoglobulin G (IgG). Membrane TPE has been shown to remove immunoglobulins with efficacy similar to centrifugal TPE. [2]

The extent of removal depends on the volume of plasma exchanged as well as the intravascular distribution and half-life of the target molecule. IgM is approximately 78% intravascular with a half-life of 5 days, whereas IgG is less than 45% intravascular with a half-life of 21 days. After each treatment, concentrations can rise over the following 24 to 48 hours because of new generation and equilibration between the extravascular and intravascular compartments. An exchange of 1 estimated plasma volume lowers pretreatment immunoglobulin concentrations by approximately 63%, while an exchange of 1.43 estimated plasma volumes lowers concentrations by approximately 75%; exchanging more than approximately 1.5 plasma volumes during a single session provides little additional removal. Ideally, medications such as IgG and therapeutic antibodies should be scheduled after plasma exchange to avoid their removal. [2]

Background References: [1] Winkelmann A, Loebermann M, Barnett M, Hartung HP, Zettl UK. Vaccination and immunotherapies in neuroimmunological diseases. Nat Rev Neurol. 2022;18(5):289-306. doi:10.1038/s41582-022-00646-5
[2] Ahmed S, Kaplan A. Therapeutic Plasma Exchange Using Membrane Plasma Separation. Clin J Am Soc Nephrol. 2020;15(9):1364-1370. doi:10.2215/CJN.12501019
Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

If a rabies vaccine is given immediately before, during, or after standing twice weekly pheresis, what is the risk of it losing efficacy due to partial or complete elimination prior to its effect on the body?

Level of evidence

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Please see Tables 1-2 for your response.


Removal Dynamics of Immunoglobulin and Fibrinogen by Conventional Plasma Exchange, Selective Plasma Exchange, and a Combination of the Two
Design

Retrospective, observational study

N= 53

Objective To investigate the removal dynamics of immunoglobulin (Ig) and fibrinogen (Fbg) in patients with immunological disorders using plasma exchange (PE), selective plasma exchange (SePE), and a combination of the two
Study Groups

PE group (n= 2)

SePE group (n= 14)

PE/SePE group (n= 4)

Inclusion Criteria Patients with immunological disorders who underwent plasmapheresis between October 2011 and June 2015
Exclusion Criteria Not specified
Methods Plasmapheresis therapies were performed using a Plasauto iQ21 blood purification system. PE was performed using a Plasmaflo OP-05 W plasma separator, and SePE was performed using the Evacure EC-4A10 selective plasma separator. Albumin solutions were used as supplementary fluids. The blood flow rate was maintained at 80–120 mL/min, and the plasma separation rate was 20–30 mL/min. Unfractionated heparin was used as an anticoagulant. The target PPVs were set at 0.9 PV in PE and 1–1.25 PV in SePE
Duration October 2011 to June 2015
Outcome Measures Percent reduction of IgG, IgA, IgM, and Fbg
Baseline Characteristics   All patients (n= 53)
Age, mean years (SD) 49.0 (±18.2)
Female 29 (55%)
Male 24 (45%)
Results   PE group PE/SePE group SePE group
IgG percent reduction 82.0% 76.4% 75.4%
IgA percent reduction 80.4% 57.7% 50.6%
IgM percent reduction 87.3% 43.3% 3.2%
Fbg percent reduction 80.9% 35.9% 29.3%
Adverse Events N/A
Study Author Conclusions When the substance targeted by plasmapheresis is limited to IgG, SePE is both a useful and safe option. When substances targeted by plasmapheresis are various Igs, PE can be combined with SePE, resulting in both the unspecific removal of pathogens by PE and retention of coagulation factors, such as Fbg, by SePE.
Critique The study was limited by its retrospective and observational nature, and the small sample size, particularly in the PE group, which may affect the reliability of the findings. Additionally, no clinical outcomes or complications were assessed, which limits the understanding of the therapeutic effects and safety of the treatments.
Table 1 References:
[3] Miyamoto S, Ohkubo A, Seshima H, et al. Removal Dynamics of Immunoglobulin and Fibrinogen by Conventional Plasma Exchange, Selective Plasma Exchange, and a Combination of the Two. Ther Apher Dial. 2016;20(4):342-347. doi:10.1111/1744-9987.12465

 

SARS-CoV-2 IgG spike protein antibody response in mRNA-1273 Moderna® vaccinated patients on maintenance immunoapheresis – a cohort study
Design

Prospective cohort study

N= 24

Objective To examine the humoral immune response after mRNA-1273 Moderna® vaccination in immunoapheresis patients
Study Groups

IgG apheresis (n= 6)

LDL apheresis (n= 18)

Inclusion Criteria Patients enrolled in the chronic apheresis program at the Medical University of Vienna, vaccinated between March 11, 2021, and April 9, 2021
Exclusion Criteria N/A
Methods Prospective monitoring of SARS-CoV-2 IgG spike protein antibody levels before and after each IgG or lipid (LDL) apheresis over 12 weeks and once after 24 weeks. Laboratory assessments were conducted at regular treatment visits.
Duration 12 weeks with an additional follow-up at 24 weeks
Outcome Measures

Primary: Difference of change of SARS-CoV-2 IgG S antibody levels from vaccination until week 12

Secondary: Difference of change of SARS-CoV-2 IgG S antibody levels by apheresis treatments across groups

Baseline Characteristics   IgG Apheresis (n= 6) LDL Apheresis (n= 18)
Gender (female) 73% 43%
Age (years) 50 (11.3) 56 (16)
Vaccination (yes) 80% 80%
Prior SARS-Cov-2 infection 13% 10%
Results   IgG Apheresis (n= 6) LDL Apheresis (n= 18) p-value
Median SARS-CoV-2 IgG S antibody level at 12 weeks 115 (IQR: 0.74, 258) 1216 (IQR: 788, 2178) 0.03
Median SARS-CoV-2 IgG S antibody reduction by apheresis 76.4% 23.7% 0.04
Adverse Events N/A
Study Author Conclusions IgG apheresis patients had lower SARS-CoV-2 IgG S antibody levels compared to LDL apheresis patients, but recovered appropriately between treatment sessions. IgG apheresis itself probably has less effect on maintaining the immune response compared to concomitant immunosuppressive drugs. Immunization is recommended independent of apheresis treatment.
Critique The study provides valuable insights into the immune response of immunoapheresis patients following mRNA-1273 vaccination. However, the small sample size and heterogeneity of the patient population limit the generalizability of the findings. Additionally, the study does not account for potential confounding factors such as varying levels of immunosuppressive medication among participants.
Table 2 References:
[4] Gaggl M, Aschauer C, Aigner C, et al. SARS-CoV-2 IgG spike protein antibody response in mRNA-1273 Moderna vaccinated patients on maintenance immunoapheresis - a cohort study. Front Immunol. 2022;13:969193. Published 2022 Sep 26. doi:10.3389/fimmu.2022.969193