key: cord-0963424-aib53pz4
authors: Schnyder, Jenny L.; de Jong, Hanna K.; Grobusch, Martin P.
title: Intradermal immunisation – A dose-sparing strategy to combat global shortages of SARS-CoV-2 vaccines?
date: 2021-08-29
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2021.08.020
sha: e79c108a86c19137616911eafb61a71c0f717d67
doc_id: 963424
cord_uid: aib53pz4

nan

Shortages in vaccine supplies are a major health problem of global concern, particularly during epidemics and pandemics, such as COVID-19. At the time of writing, merely 13.0% of the world's population had been fully immunised against SARS-CoV-2, leaving 6.9 billion people worldwide still unprotected [1] . Therefore, dose-sparing approaches such as intradermal (ID) vaccination should be considered in mass immunisations. Numerous studies over the past decades showed that for several vaccines (e.g. rabies, influenza and hepatitis B) doses can be reduced by using ID immunisation as an alternative to intramuscular (IM) and subcutaneous (SC) immunisation, without the loss of vaccine immunogenicity and efficacy, thereby augmenting vaccine supply utilisation [2] . The target layer for intradermal immunisation is the papillary dermis, which is rich in antigen presenting cells (APCs) (namely Langerhans cells and dendritic cells). APCs capture antigens deposited in the dermis and migrate through lymphatic vessels to lymph nodes. Here, APCs present the antigens to Tand B-cells, triggering activation. Due to the abundance of APCs in the dermis, stimulating adaptive immune responses, reduced doses of antigen can be used when applied intradermally [3] .

Over the past decades, a vast number of clinical trials has been published comparing fractional dose ID immunisation to standard routes of immunisation. A recent systematic review and meta-analysis provided an overview of the literature, including 156 studies comparing fractional ID to IM/SC immunisation covering 12 vaccines [2] . For ID influenza, rabies and hepatitis B vaccines, non-inferiority of immunogenicity was demonstrated when administrating 20-60% of antigen compared to standard routes of immunisation. For J o u r n a l P r e -p r o o f inactivated polio and measles vaccines, it remained uncertain if doses can by reduced by the use of ID administration, as the results of these studies varied. Clinical trials on other vaccines (i.e. hepatitis A, diphtheria-tetanus-pertussis, human papilloma virus, Japanese encephalitis, meningococcal disease, varicella zoster and yellow fever vaccines) yielded promising results, but are both scarce and limited with regard to numbers of participants.

Mainly during outbreaks, when there is an increased demand for vaccines, serious shortages have occurred in the past. Vaccine shortages and stock-outs are a serious public health issue, affecting prevention and control programmes of infectious diseases, and can lead to critical reduction in population coverage. Whilst there are limits to fractionating standard IM or SC vaccine doses [4] dose-sparing strategies such as ID immunisation can help to battle vaccine shortages. To date, the WHO approved ID administration of three marketed vaccines: rabies vaccine, inactivated poliovirus vaccines, and tuberculosis vaccine, using the live attenuated Bacillus Calmette-Gúerin (BCG) strain of Mycobacterium bovis [5, 6] . Ever since, ID rabies immunisation has been introduced to combat vaccine shortages at a national level by resource-constrained countries such as India, Thailand and the Philippines [7] .

Although the dose-sparing potential for certain vaccines has clearly been established, still some barriers need to be overcome, and more data are needed, so evidence can be turned into action. Firstly, there are technical challenges that vaccinators may encounter.

Intradermal vaccination is a more complex vaccination technique, which requires training.

Though, training can be very effective and time-efficient, especially with the assistance of J o u r n a l P r e -p r o o f novel ID application devices [3] . Additionally, there might be reservations about the accuracy of ID application of antigen. However, this is easily verified by the appearance of a wheal of > 5 mm in diameter, which indicates correct administration of 0.1 ml of vaccine solution [3] .

Another concern of ID delivery is the higher rate of local reactions at injection site, including redness, swelling and itching. Systemic adverse events, on the other hand, are not more common after ID delivery, and comparable to IM/SC immunisation [2] .

Another major bottleneck for implementing ID administration into routine care lies with regulatory issues. When a fractional dose of an existing vaccine is applied intradermally, it is often off-label use, as the vaccine is intended for IM/SC use [3, 7] . Therefore, national However, clinical trials including ID arms are needed to determine for which SARS-CoV-2 vaccines dose-sparing by ID immunisation could be an option.

Recently, two clinical trials have initiated assessing the safety and immunogenicity of fractionally dosed ID compared to standard IM delivery of registered SARS-CoV-2 vaccines [8, 9] . The first ongoing study is a Dutch randomised clinical trial on healthy adults comparing the immunogenicity of ID delivery of two fractional doses of 10 μg and 20 μg of mRNA-1273 vaccine (Moderna®) with that of two doses of 20 μg and 100 μg (standard dose) through IM delivery [8] . In a recent press release, the investigators stated that the phase I/II study showed promising results, and a phase III study will start soon [10] . Another clinical trial that recently started and takes place in Belgium, investigates adapted vaccine schedules and routes, including fractional dose ID delivery of 6 μg (1/5 th of standard dose) of BNT162b2 (Comirnaty®) and 0.1 ml (1/5 th of standard dose) of ChAdOx1 (Vaxzevria®), and comparing those with standard route and doses [9] . Depending on the results of these trials, we prompt policy-makers to consider the introduction of ID regimens of these registered SARS-CoV-2 vaccines to lower costs and significantly increase vaccine supplies. Especially in low-income settings, the paucity of SARS-CoV-2 vaccines is a most pressing issue, and dose-sparing solutions are warranted. According to recent estimates by researchers from the Duke Global Health Innovation Centre the world's population is expected to be vaccinated against SARS-CoV-2 in 2023, which is still two years from now [11] . However, if ID immunisation with 1/5 th of standard vaccine dose renders effective, this period could hypothetically be shortened to J o u r n a l P r e -p r o o f only six months. Given the urgency of that matter, we indeed advocate for considering investigating fractional-dose ID arms as early as dose-finding studies have determined optimal dosing of standard applications for novel and re-engineered SARS-CoV-2 vaccines.

A relatively new class of vaccines are the mRNA vaccines. Over the past decade, mRNA vaccines have been increasingly recognised as a promising tool for both preventing infectious diseases and as cancer immunotherapy. However, it was not until the COVID-19 pandemic, that the first two mRNA vaccines were approved for human use, namely the mRNA-1273 vaccine (Moderna®) and BNT162b2 vaccine (Comirnaty®). After administration, the mRNA, encoding a target antigen, is internalised by host cells. Subsequently, ribosomes in the cytoplasm translate the mRNA, resulting in the production of the target protein. This antigen will be presented to immune cells, mounting an adaptive immune response against the target protein. As the dermis is rich in antigen-presenting cells, it is the ideal site for delivery of mRNA, encoding the antigenic protein. Therefore, the ID delivery route is widely used for mRNA cancer vaccines [12] . Recently, there has been a huge amount of investment in mRNA vaccine companies developing in both mRNA cancer vaccines and mRNA vaccines against infectious diseases [11] . Thus, we expect more mRNA vaccines to become registered and marketed over the next couple of years. We prompt vaccine developers of novel mRNA vaccines against infectious agents that are still at an early stage, to include fractional-dose ID arms, as shortages in vaccine supplies are an ongoing major health problem contributing to the prolonged duration of the current COVID-19 pandemic.

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