Influenza vaccines – a needle-free option?

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Annual vaccines against seasonal influenza are offered in some capacity in many countries across the globe. In the USA, the Centers for Disease Control and Prevention (CDC; GA, USA) recommends that everyone aged over 6 months, who doesn’t have a contraindication, receives an annual flu vaccination. However, uptake can be poor; for example, in the 2015–2016 season coverage was only 41.7% of US adults [1].

Many factors may influence an individual’s decision to not get the vaccine, including safety concerns or false beliefs that the side effects of vaccination are worse than the disease itself [2]. Although it might not address all concerns, it has been argued that a simple, efficacious delivery method could improve vaccination rates and health outcomes with regards to the flu vaccine – leading us to ask – could a nominally ‘needle-free’ option be the answer?

The FluMist Story

Although a needle-free option is available in the US in the form of FluMist® – a live attenuated influenza vaccine administered as a nasal spray – last year the CDC recommended against the use of this vaccine “in any setting” for the 2016–2017 flu season [3]. This was a result of vaccine effectiveness data from the previous three flu seasons indicating that FluMist didn’t demonstrate significant effectiveness in children, who are the primary recipients. The company behind FluMist, AstraZeneca (Cambridge, UK), contradicted this data, releasing findings suggesting the vaccine was 46–58% effective during the 2015–2016 season, compared with the flu shot’s 65% effectiveness [4], however the CDC recommendation stood.

In June this year, and despite efforts to improve the inhaled vaccine including a letter published in Eurosurveillance outlining hypotheses for the reduced effectiveness [5], the CDC again recommended against the use of FluMist for the upcoming 2017–2018 flu season.

There was some concern that, as the USA’s only non-injectable flu vaccine, the removal of FluMist from the CDC recommendations could further affect vaccine uptake rates, and compromise the US’ response in the event of a flu pandemic. However, according to preliminary data, the 2016 exclusion of FluMist did not affect vaccine coverage [6]. In addition, even when it was in widespread use, FluMist was only FDA-licensed for use in those aged 2–49 years [7] and not populations such as the elderly, who present a high-risk population in terms of flu mortalities and therefore are a priority for vaccination.

A new approach?

Microneedles

There could be new alternatives to traditional intramuscular injection on the horizon, for example, a recent Phase I clinical trial presented promising results for a single, dissolvable microneedle patch vaccination against influenza [8].

The trial, published in The Lancet, assessed the safety and efficacy of a microneedle flu patch in 100 volunteers vaccinated between June and September 2015. Participants were randomly assigned to one of four groups: microneedle patch vaccine administered by a healthcare; self-administration of the microneedle patch vaccine; placebo microneedle patch administered by a healthcare provider and traditional flu vaccination.

The findings for patient experience were positive, for example, immediately after vaccination 96% of adults receiving the patch reported no pain, compared with only 82% of the traditional shot group. In addition, side effects of the patch were similar compared to the traditional flu shot and, at the 28-day follow-up, 70% of the patch group stated they would prefer to receive the patch to the injection [9].

Moreover, the patch proved effective as a vaccine – mean viral titres for the patch were significantly higher than the placebo and were similar when compared to traditional injection. The study also reported that titres were similar between the microneedle patch administered by a healthcare professional versus self-administration [9].

This is not the only microneedle patch developed for influenza, Osaka University (Japan) and CosMED Pharmaceutical Co. Ltd. (Kyoto, Japan) have also developed a dissolvable patch composed of hyaluronic acid, which produced an immune response equal or greater to that induced by vaccination via hypodermic needle when tested in a small trial of 40 volunteers (in 2015) [10].

However, it is the confirmed potential for self-administration demonstrated by the recent trial that is one of the most promising aspects for this ‘needle-free’ vaccine. It is thought this capacity may improve vaccine uptake as, not only is it more user-acceptable than traditional options, it would also reduce some of the efforts required to obtain the vaccine. Lead author of the trial, Nadine Rouphael (Emory University, GA, USA) expanded:  “It would remove the bottleneck of actually going to a health care provider to receive the vaccine, and it could put people less at risk of acquiring influenza in the hospital and clinic by just receiving it at their home.”

In addition, self-administration could be useful in the case of a widespread influenza outbreak and, if rolled out, could reduce public health costs and healthcare administration fees. This approach also holds a lot of appeal for increasing vaccine uptake in low-resource or remote settings as the patch is thermally stable therefore does not require a ‘cold chain’.

In a report published in Vaccine, these benefits were echoed by key opinion leaders, who stated that microneedle patches had the potential to “help increase coverage, facilitate easy and safe delivery, reduce the cost of vaccination, and decrease the global morbidity and mortality associated with influenza.” [11]

Oral administration

Microneedle patches are not the only approach being investigated. Previous decades have seen research on an oral influenza vaccine; however, despite candidates producing good mucosal immunity, they did not generate a serum antibody response and therefore did not pass regulatory criteria [12].

More recently there has been renewed interest in an oral, tablet-based influenza vaccine. Pioneered by Vaxart (CA, USA), a company dedicated to oral vaccines, two tablets are currently in clinical trials – one for influenza A and one for influenza B – with the aim of ultimately producing a quadrivalent oral vaccination.

The tablet for influenza B is being assessed in a Phase I, single-center, placebo-controlled, double-blind study to determine safety and immunogenicity. The trial will assess low and high doses of the vaccine, with 27 participants in each cohort randomized 2:1 vaccine: placebo. Measures such as immunogenicity and adverse effects will be monitored at day 28 post-immunization and individuals will be followed up for a year [13].

In addition, the company are currently undertaking a Phase II trial for their influenza A tablet, funded by the Biomedical Advanced Research and Development Authority (DC, USA). The Phase I results were positive, demonstrating the generation of neutralizing antibodies and a mucosal immune response in 92% of participants after a single vaccine dose [14]. The Phase II study will therefore test this adenovirus-based vaccine in a challenge study. The company are aiming to recruit an estimated 180 participants aged 18–49, who will either receive the tablet vaccine and a placebo injection, a placebo tablet and a injected vaccine or a tablet and injection, both of which are placebos. Participants then will be challenged with influenza A H1N1 approximately 90 days post-vaccination and the team will subsequently assess for immunogenicity and safety parameters of the tablet approach during a year-long follow-up [15].

As one of the only oral influenza vaccines in clinical trials Vaxart hope that their tablets will provide an effective vaccine, with advantages in distribution and ease of administration compared to tradition intramuscular injections.

Conclusions

There have been other approaches to producing a needle-free influenza vaccine not discussed here, for example, pulmonary vaccination via an aerosol or epidermal powder vaccination – both of which have had some promising pre-clinical and clinical results [12].

The volume of research into alternative approaches appears to demonstrate the shortcomings of the current intramuscular seasonal influenza vaccine. One solution being investigated is producing a single-dose universal vaccine to reduce the necessity for multiple injections; however, with this a long way off, perhaps the alternative is to make seasonal vaccinations more acceptable and accessible. ‘Needle-free’ delivery systems have these benefits, demonstrating increased convenience, acceptance, reduced medical waste, and perhaps, in the future, could help reduce some of the fear and stigma surrounding annual vaccination.

References
  1. Centers for Disease Control and Prevention. 2015–16 Flu Season. cdc.gov/flu/fluvaxview/1516season.htm (Accessed 27th September 2017)
  2. Bish A, Yardley L, Nicoll A & Michie S. Factors associated with uptake of vaccination against pandemic influenza: A systematic review. 29(31) 6472–6484 (2011)
  3. Centers for Disease Control and Prevention. Advisory Committee on Immunization Practices (ACIP) Meeting information. cdc.gov/vaccines/acip/meetings/meetings-info.html (Accessed 27th September 2017)
  4. AstraZeneca provides update on Flumist Quadrivalent Vaccine in the US for the 2016-17 influenza season. www.astrazeneca.com/media-centre/press-releases/2016/astrazeneca-provides-update-on-flumist-quadrivalent-vaccine-in-the-us-for-the-2016-17-influenza-season-23062016.html (Accessed 27th September 2017)
  5. Mallory R, Bright H, Ambrose CS. Letter to the editor: Potential causes of the decreased effectiveness of the influenza A(H1N1)pdm09 strain in live attenuated influenza vaccines. 21 (45) (2016)
  6. Centers for Disease Control and Prevention. 2016–17 Flu Season. https://www.cdc.gov/flu/fluvaxview/1617season.htm (Accessed 27th September 2017)
  7. FluMist prescribing information. fda.gov/downloads/biologicsbloodvaccines/vaccines/approvedproducts/ucm294307.pdf (Accessed 27th September 2017)
  8. Infectious Diseases Hub. Phase I trial results promising for flu vaccine microneedle patches. www.id-hub.com/2017/06/28/phase-trial-results-promising-flu-vaccine-microneedle-patches (Accessed 27th September 2017)
  9. Rouphael NG, Paine M, Mosely R et al. The safety, immunogenicity, and acceptability of inactivated influenza vaccine delivered by microneedle patch (TIV-MNP 2015): a randomised, partly blinded, placebo-controlled, phase 1 trial. The Lancet. 390 (10095) 649–658 (2017)
  10. Hirobe A, Azukizawa H, Hanafusa et al. Clinical study and stability assessment of a novel transcutaneous influenza vaccination using a dissolving microneedle patch. 57, 50–58 (2015)
  11. Jacoby E, Jarrahian C, Hull HF, Zehrung D. Opportunities and challenges in delivering influenza vaccine by microneedle patch. 33 (37) 4699–4704 (2015)
  12. Kang S. Song J, Kim Y. Microneedle and Mucosal Delivery of Influenza Vaccines. Expert Rev Vaccines. 11(5), 547–560 (2012)
  13. Assessment of an Oral Influenza B Vaccine Tablet (VXA-BYW.10) Following Single Dose Administration in Healthy Adults. https://clinicaltrials.gov/ct2/show/NCT02547792 NLM identifier: NCT02547792
  14. Vaxart announces enrolment of first patient in influenza B Phase I trial. http://vaxart.com/NewsNewsReleases.html (Accessed 27th September 2017)
  15. A Phase 2 Influenza A Challenge Study Following Oral Administration of an H1N1 HA Ad-Vector Seasonal Flu Vaccine. https://clinicaltrials.gov/ct2/show/NCT0291800 NLM identifier: NCT02918006
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