What news can you tell us about the current state of the pandemic?
Current discussions on COVID-19 are dominated by two topics:
- The emergence of Sars-Cov2 mutations of concern, and
- The high demand of vaccine doses and measures how to meet it.
Ever since the sequence of the genome of SarsCov2 has been published in January 2020, a high number of companies started out to develop a vaccine to combat the following pandemic. To date a total of 13 companies have successfully entered their candidates into Ph III studies. The latest players in this game are Curevac with their CVnCoV mRNA candidate, Clover pharmaceuticals with their protein subunit COVID/19 S/Trimer, Medicago with their plant-derived Corona-Virus-like Particle (VLP) CoVLP composed of a recombinant Spike (S) Protein expressed as a VLP, and Zydus Cadila with their DNA plasmid vaccine plus adjuvant. If the latter concludes its PH III trials successfully, it would be the first ever DNA-based vaccine to obtain registration for human use. The same held true for the two mRNA vaccines developed by BioNTech/Pfizer and Moderna that already received emergency use or other registrations earlier. The search to find means to control the spreading pandemic led to accelerated scientific developments and major achievements in this field.
Despite this, the current mood is somewhat subdued. The reason for this is the emergence of new mutations.
Why is this a concern?
SarsCov2 has been mutating ever since it started spreading. The new variants, however, are characterized by a significantly increased transmissibility. This is of concern as it will lead to higher case numbers and an increased number of COVID19-associated deaths. Measures to control the spread of the virus and keep the reproductive number R below 1 may become ineffective. If the new variants are 50% more transmissible, the percentage of the population that needs to be vaccinated to achieve herd immunity rises from 60-75% to 73-85%.
Moreover, it would be beneficial to counteract the spread of the new variants with vaccination programs and other measures, in order to prevent or at least slow down the process of the new variants becoming dominant in a population. And lastly, many of the vaccines that have been developed so far have shown reduced or greatly reduced efficacy with respect to the new mutants. Meaning that some of the current vaccines no longer offer real protection against the virus (so-called vaccine escape).
All of this poses several problems: 1) At this time there is not yet a sufficient volume of doses available to quickly vaccinate with the current vaccines a high number of subjects, in areas where the new mutants are not yet wide-spread. 2) With these new R numbers, vaccination willingness may start to become an issue with respect to the goal of achieving herd immunity. 3) Vaccines will need to be adapted quickly to continue to be efficient against the virus.
So what is being done to boost vaccine supply?
The mRNA vaccine developed by BioNTech and Pfizer is already available in many countries. BioNTech recently announced that they will streamline production processes and thereby increase the annual volume of doses from 1 billion to 2 billion for 2021. To achieve this, they just started production in their new plant in Marburg. Also, Sanofi whose own vaccine candidate is delayed in clinical development entered into an agreement to produce another 100M doses for BioNTech at their facilities.
Moderna has its vaccine manufactured by Swiss contract drug manufacturer Lonza and fill-finishes it with the help of Catalent. They plan to produce 600 M – 1 Bn doses in 2021. Moreover, they recently bought an additional facility in South Korea to boost production.
AstraZeneca initially planned to produce 2.5 to 3 billion doses in 2021, however, faced some supply issues recently.
J&J have already filed for emergency use authorization in the US and got the approval of the FDA on 28th of February. Their vaccine candidate is an adenovirus vector. The EMA is expected to recommend on this vaccine on March 11th. The EMA is expected to recommend on this vaccine on March 11th.
Chinese vaccine manufacturers SinoVac, SinoPharm and Cansino as well as Indian company Bharat BioSciences deliver their vaccines mainly within their own countries as well as to South East Asia, the MENA region and Latin America. The Russian adenovirus vector “Sputnik V” is also delivered to India, Latin America and Asia and the EMA has recently started their rolling review of this adenovirus vector vaccine (also called Gam-COVID-Vac). It is interesting to note that the developing Russian Gamaleya Institute has used 2 different adenoviruses as carriers for the Sars-CoV-2 spike protein genetic material for the first and second jabs. This is supposed to lead to increased immunogenicity.
German Biopharmaceutical company CureVac has successfully completed a Ph III study with 15 000 subjects and are currently enrolling into their pivotal PH II/III study with 36 500 subjects. Recently they started the rolling review process with the EMA (European Medicines Agency). Curevac has contracts in place with Bayer, GSK, Rentschler, Wacker and Novartis to produce ~ 1 Bn doses of the vaccine for them in 2021.
Canadian drug maker Novavax is currently enrolling into their Ph III study of adjuvanted SARS-CoV rS recombinant Spike Protein Nanoparticle with an aim of 30 000 participants. Preliminary data on thier vaccine candidate showed an efficacy of 96% against the wild type of Sars-Cov-2 and of 86% against the new UK variant. Novavax expects FDA approval in May 2021.
So while billions of doses may be available in 2021, the current supply is still low. Several methods are being tested to inoculate more people with a defined volume of doses:
AstraZeneca was able to demonstrate that their vaccine ChAdOx1 nCoV-19 or AZD1222 is even more effective if the jabs are given 12 weeks apart instead of 3 to 4. That way there is no longer a need to withhold vaccine doses to be administered after 4 weeks for the necessary second jab. That way more people will get their first vaccination.
Moreover, research is under way to check if vaccines may be mixed, i.e. if the second inoculation may be from a different company, based on another platform. BioNTech and AstraZeneca are currently investigating this. If it proves permissible to mix and match the shots, the need to store second shots would be greatly diminished, thereby allowing the vaccination of many more people with the currently available supplies (most vaccines require 2 shots to gain immunity).
What can be done to tackle the emerging virus mutations of concern?
It has been shown that current multiple mutations in the gene coding for the spike protein ultimately lead to vaccine escape. Current vaccines will be used to inoculate subjects and will lead to immunity to the initial variants of the virus but going forward it will be necessary to adapt the vaccines to the newly emerging virus mutations.
Both AstraZeneca and Curevac are already in the process of exploring the efficacy of new, adapted vaccine candidates. Moderna is testing various booster shots with a new formulation for their efficacy against the more resistant South African lineage.
From a regulatory perspective, the FDA already announced that they will lay out a speedy path of approval for vaccinations against COVID19 variants.
What are the plans to achieve buy-in of the population to get vaccinated?
Once enough doses of vaccines become available the goal will be to achieve herd immunity. At this time, willingness to get vaccinated may become a limiting factor. Studies had shown that in many Western countries, only about 60% of the population actually planned to take the jab.
Fortunately, now that vaccination is under way, concerns about side effects or rare reactions are decreasing as there are only few reports of negative occurrences after getting inoculated. A recent study in the US revealed that vaccination willingness is at ~ 80%. Another survey in German citizens allowed the conclusion that willingness is increasing rapidly after having reached an all-time low in December.
Campaigns and, most importantly, information on how vaccines work and how to assess the (very small) risk of side effects need to be disseminated by authorities, doctors and health insurances.
In many countries on all continents the vaccinations have started, aiming on delivering the jab to 20% of the population in a first step with those who work in (health)care, the elderly and those with underlying health conditions as a priority. It is expected that the vaccination willingness of the general population will further increase once it has seen the positive results and impact of the first 20% that received a vaccination.
What does this all mean for vaccine supply chain and distribution?
Current vaccines require several very different temperature ranges for transport. The new vaccines developed by Curevac, Zydus Cadila, Medicago and Clover Pharmaceuticals all require +2 to +8°C for transport. Curevac’s mRNA vaccine candidate has been reported to be stable at +2 to +8°C for up to 3 months. It may be expected, though, that with it being an mRNA vaccine, the best long-term storage temperatures may actually be -78°C/ (dry ice). Clover’s Protein subunit vaccines requires +2 to +8°C for storage and transport as expected.
Zydus Cadila are the first vaccine manufacturers to potentially gain registration of a DNA vaccine for the use in humans. DNA is usually stored at -20°C to -40°C, but the company confirmed that the vaccine may be kept for longer time periods at +2 to +8°C and is even stable at room temperature for up to 3 months. DNA, due to its structural differences, is more stable than mRNA.
In summary, the newly arrived vaccine candidates will not neccessitate further adaptations of the cold chain.
The information shared above, however, leads to the following conclusion:
If the virus continues to evolve, mutations that escape the vaccines will continue to emerge. As a consequence, vaccines will have to be continuously adapted, and there will be a constant requirement for the administration of coronavirus booster shots to the public to prepare them for the new variants. Thus COVID19 may ultimately have to be treated somewhat like the flu, with recurring vaccinations administered at certain intervals.
This means there will be a continuous demand for materials used in vaccine transport and manufacturing, as well as a continuous demand of logistic activities, be it by plane, lorry or other means.
Both the supply and distribution of the vaccines is currently behind what is needed to achieve herd immunity. And while there are many promising signals, it will take months to close the gap.
The mutations of the virus occurred in all corners of the world. This underlines the principle that as a global community, we are only safe once everyone is safe. Thus ensuring that vaccines are also available in low-and middle-income countries (LMICs) is in the interest of every citizen in the world. Currently three quarters of the available vaccine doses have been administered in just 10 countries which however represent ~60% of the global GDP.
Berlinger supports the call for action by the WHO to achieve vaccine equity, to ensure that everyone in the world has access to vaccines. The COVAX facility is set up to do just that, by supporting self-financing countries and funding LMICs to gain access to the same vaccine portfolios as the more affluent countries have.
What else needs to be considered, besides vaccine availability
In parallel to making the vaccines available, the cold chain needs to be prepared for these vaccines. With different vaccines and various temperature ranges this means reviewing the existing cold chain equipment and competencies of staff. Based on that review a targeted improvement of competencies and equipment might be required. Both of these investments take time, and the pre-pandemic approaches for such investments might no longer be fit for purpose in the new normal.
National health authorities are leading the reviews and capacity building of staff, despite the restrictions and limitations of the pandemic measures. Simultaneously manufacturers are supplying as quickly as possible, while adjusting to the new normal for installation, commissioning, training and maintenance, and despite the global disruptions in global freight, national lockdowns, volatility in the supply of parts and local outbreaks of the virus.
Moreover, starting in 2020 we have seen an increased emphasis on and need for temperature ranges that are new for the vaccine transport business. Prior to this pandemic vaccine storage was mainly focussed on temperature ranges of +2 to +8°C, while we are now also challenged to provide solutions for ultra-low temperatures (-70°C and lower) and, with increasing frequency, for freezing temperature ranges (-25 to -15°C).
In the bigger scheme of fighting the pandemic, these may be seen as minor new developments, yet they are vital for those individuals who will benefit from the COVID19 vaccines.