Vaccines and treatment of COVID-19

Vaccine (Latest update 10 August 2020)

There is a large global effort to develop vaccines for protection against COVID-19 and at least 19 vaccine candidates have, as of 31 July 2020, entered clinical trials, including phase 2 and 3 trials [1].

Established and new vaccine production technologies are being used for development of COVID-19 vaccine candidates: whole-inactivated virus, live attenuated virus, protein subunit, replicating and non-replicating viral vectors expressing SARS-CoV-2 proteins as well as DNA and RNA technologies delivering gene sequences that encode SARS-CoV-2 proteins that then are produced by host cells [2].

Safety and immunogenicity data have been reported in the scientific literature for phase 1 trials assessing a vector-based SARS-CoV-2 vaccine candidate conducted in China [3] and a mRNA SARS-CoV-2 vaccine candidate conducted in the US [4]. Further, results from a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control have been reported. Healthy adults aged 18–55 years with no history of laboratory-confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 1010 viral particles or MenACWY as a single intramuscular injection [5]. There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 Anti-spike IgG responses rose by day 28 , and were boosted following a second dose [5]. Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose. . After a booster dose, all participants had neutralising activity.

EMA has been, as of 30 July 2020, in discussion with developers of 38 potential COVID-19 vaccines. However, the EMA estimates that it might take at least until the beginning of 2021 before a vaccine against COVID-19 is ready for approval and available in sufficient quantities to enable widespread use in the EU/EEA [6].

The opportunities and challenges of developing vaccines against COVID-19 are discussed widely [7,8] and important lessons from SARS-CoV-1 vaccine development may guide SARS-CoV-2 vaccine design, testing, and implementation [9]. A major challenge during rapid development is to avoid safety issues. A syndrome of "disease enhancement" has been reported in the past for a few viral vaccines where those immunized suffered increased severity of infection or death when they later encountered the virus. Since some SARS-CoV-1 vaccines have shown evidence of disease enhancement in some animal models, this is a concern for SARS-CoV-2 vaccines as well

Pharmaceutical prophylaxis and treatment 9 (Latest update 22 July 2020)

There are several large-scale, multicentre trials underway that are using an appropriately robust methodology for assessment of potential therapeutics, including the WHO Solidarity Trial, several United States National Institutes of Health and national trials in several EU Member States [10,11]. Encouragement of the enrolment of patients in these clinical trials would expedite their successful and timely completion. Pharmaceuticals undergoing clinical trials to assess their safety and efficacy as potential treatments for COVID-19, include the antiviral nucleotide analogue remdesivir, systemic interferons and in particular interferon β-1a, the antiviral combination lopinavir/ritonavir, the antimalarial chloroquine/hydroxychloroquine, and monoclonal antibodies against components of the immune system such as interleukin-6 (IL-6) and IL-4 [12]. It is important that the potential treatments are carefully assessed in randomised controlled trials.

On 16 June 2020, preliminary results of a randomised, controlled, open-label, adaptive clinical trial of dexamethasone were published. Dexamethasone significantly reduced the 28-day mortality, particularly among critically ill COVID-19 patients receiving mechanical ventilation. There was no evidence of benefit for patients not requiring oxygen [13,14]. Based on these findings, the US National Institutes of Health (NIH) recommends the administration of dexamethasone for COVID-19 patients who are either mechanically ventilated or require supplemental oxygen [15].

Preliminary results from 1 059 hospitalised COVID-19 patients enrolled in a double blind randomised controlled trial showed that remdesivir was associated with shorter median recovery time compared to placebo (11 vs. 15 days). The 14-day mortality was 7.1% in the group of patients that received remdesivir and 11.9% in the placebo group but the difference was not statistically significant [16]. On 25 June 2020, EMA’s human medicines committee (CHMP) recommended that remdesivir is granted a conditional marketing authorisation for the treatment of COVID-19 patients with pneumonia requiring supplemental oxygen [17]. On 3 July 2020, the European Commission granted conditional marketing authorisation for the treatment of COVID-19 in adults and adolescents from 12 years of age with pneumonia who require supplemental oxygen [18], making remdesivir the first authorised COVID-19 antiviral treatment in the EU.

Hydroxychloroquine (HCQ) has been shown in vitro to alter the uptake of the virus in cells, and small case series and a small trial had reported its use in patients during the early phases of this outbreak in China and Europe in combination with azithromycin, with conflicting results. Subsequently, in June preliminary results of a large randomised controlled trial (Randomised Evaluation of COVid-19 thERapY - RECOVERY) that compared 1 542 patients that were randomised to hydroxychloroquine (HCQ) with 3 132 patients that received usual care did not find any difference between the two groups in mortality, hospital stay or other outcomes [19]. The authors concluded that any meaningful benefit of HCQ for the treatment of COVID-19 has been ruled out and discontinued randomisation in the hydroxychloroquine arm. On 17 June 2020, WHO announced that the SOLIDARITY trial will discontinue the HCQ arm based on evidence from the trial, but also on the preliminary results of the UK’s RECOVERY trial and a Cochrane review [10]. Similarly, two clinical trials that investigated the effect of HCQ when started early (within 4-5 days from symptom onset) in non-hospitalised patients with mild symptoms, did not show any significant effect on symptom severity [20], disease progression or time to resolution of symptoms [21]. Hydroxychloroquine has also been studied for post-exposure prophylaxis in a randomised controlled trial that enrolled 821 individuals with household or occupational exposure to confirmed COVID-19 cases [22]. The study did not show a statistically significant difference in the incidence of illness compatible with COVID-19 between the group receiving hydroxychloroquine and the group receiving placebo.

A randomised, controlled, open-label trial of lopinavir/ritonavir in 199 COVID-19 patients in China did not show any statistically significant favourable effect on the clinical course or mortality when compared to standard treatment [23]. Similarly, a preliminary analysis of the UK RECOVERY trial that randomised 1 596 patients to lopinavir-ritonavir and compared with 3 376 patients randomised to usual care, identified no benefit of lopinavir/ritonavir on survival, the clinical course or the length of hospital stay [24]. The study did not include a sufficient number of subjects under invasive mechanical ventilation to allow the study of the effect of lopinavir/ritonavir in this category of patients, due to the difficulty of administration of the drug in such cases. Both the WHO SOLIDARITY and the UK RECOVERY trials discontinued the lopinavir/ritonavir arms after interim analysis of the trial results [10,25].

Reports that non-steroidal anti-inflammatory drugs worsen COVID-19 through increased expression of angiotensin-converting enzyme 2 (ACE2), whose receptor is used by SARS-CoV-2 to enter the target cells, are not supported by evidence [26].  

ACE-inhibitors and angiotensin receptor blockers are used for the treatment of hypertension, heart failure or renal disease. Patients receiving these agents are advised not to interrupt their treatment and there is no need to switch to other medicines [27].

Convalescent plasma (plasma with antibodies from recovered COVID-19 patients) is under investigation for the treatment of patients with COVID-19. Despite some study limitations, the improved outcomes in recipients of convalescent plasma obtained in two recent studies in China [28,29] support the possibility of investigating this therapy further in adequately designed clinical trials. The collection and clinical use of convalescent plasma for the treatment of COVID-19 patients is ongoing in the EU/EEA and the USA [30] within clinical studies or as an emergency compassionate use. In EU/EEA Members States, these activities are carried out according to EC guidance developed in collaboration with ECDC, national competent authorities and other stakeholders [31]. The early studies showed that convalescent plasma infusion to COVID-19 patients is safe and effective [32,33]. As of 29 May 17 674 units of convalescent plasma have been infused to COVID-19 patients in the USA [34].