New since 1 November
[23 November] On November 23, Oxford University and AstraZeneca announced that their vaccine candidate AZD1222 was highly effective in preventing COVID-19. No hospitalizations or severe cases of the disease were reported in participants receiving the vaccine. One dosing regimen (n=2741) showed vaccine efficacy of 90% when AZD1222 was given as a half dose, followed by a full dose at least one month apart, and another dosing regimen (n=8895) showed 62% efficacy when given as two full doses at least one month apart. The combined analysis from both dosing regimens (n=11,636) resulted in an average efficacy of 70%. AstraZeneca will soon request an authorization for early approval. In addition, the company will seek an Emergency Use Listing from the World Health Organization for an accelerated pathway to vaccine availability in low-income countries. AZD1222 is a chimpanzee adenovirus vaccine vector which has been genetically changed so that it is impossible for it to grow in humans. It contains the full-length, unmodified spike glycoprotein of SARS-CoV-2.
AZD1222 will be less expensive and easier to store than the mRNA vaccines by BioNTech/Pfizer and Moderna (see below). It can be stored and transported at a temperature between 2 and 8 degrees Celsius and kept for six months.
Figure 0. A diagram showing how the Oxford COVID-19 vaccine works. A chimpanzee adenovirus is used in the ChAdOx1 viral vector, engineered to match the SARS-CoV-2 spike protein. Copyright: University of Oxford. Reproduced with permission.
[Week 47 – 22 November] On 20 November, BioNTech and Pfizer announced that they had submitted a request to the US Food and Drug Administration for an Emergency Use Authorization of their COVID-19 vaccine candidate BNT162b2. Two days before, the two companies announced that the primary efficacy analysis showed BNT162b2 to be 95% effective against COVID-19 beginning 28 days after the first dose. Of 170 confirmed COVID-19 cases, 162 occurred in the placebo group and 8 in the vaccine group. Efficacy was consistent across age, gender, race and ethnicity. In particular, the observed efficacy in adults over 65 years of age was above 94%. If approved, the vaccine could be available by the end of December 2020. Find a press article at https://www.nytimes.com/2020/11/21/us/politics/coronavirus-vaccine.html.
On 16 November, Moderna announced that its vaccine candidate had met the primary efficacy endpoint in the first interim analysis of a Phase III study. An independent data-safety committee found that 95 trial participants had developed COVID-19 – 90 were in the placebo arm and 5 in the vaccine arm of the trial (vaccine efficacy: 94.5%).
Both the BioNTech/Pfizer and the Moderna vaccine candidates are based on messenger RNA (mRNA) technology. mRNA is comparable to a software code which instructs human cells (the ‘operating system’) to produce a SARS-CoV-2 protein. Once introduced into a cell, the mRNA molecule will be read by a ribosome and translated into the SARS-CoV-2 spike protein (see figure below). The spike protein will migrate to the cell surface where it will be recognized by the immune system as other and trigger an immune response.
How long (years?) might SARS-CoV-2 immunity last, was recently explored by Dan JM, Mateus J, Kato Y, et al. Immunological memory to SARS-CoV-2 assessed for greater than six months after infection, bioRxiv 2020, posted 16 November. Full-text: https://doi.org/10.1101/2020.11.15.383323. See also the press article by Mandavilli A. Immunity to the Coronavirus May Last Years, New Data Hint. The New York Times 2020, published 17 November. Full-text: https://www.nytimes.com/2020/11/17/health/coronavirus-immunity.html.
Figure 00: Ribosomes assemble protein molecules whose sequence is controlled by the sequence of messenger RNA molecules. The growing peptide chain (top left) will form the SARS-CoV-2 spike protein. tRNA: transfer RNA.
[Week 46 – 15 November] On 9 November, BioNTech and Pfizer announced that their vaccine candidate BNT162b1 (page 223) had been found to be more than 90% effective in preventing COVID-19 in participants. Efficacy data from two other vaccine trials (AstraZeneca and Moderna) are expected this month, too. It now seems reasonable to assume that the first coronavirus vaccines could be rolled out less than a year after the discovery of SARS-CoV-2.
The BioNTech/Pfizer analysis evaluated 94 confirmed cases of COVID-19 in the participants of their Phase III trial. Two days later, the European Union ordered 200 million doses on behalf of all EU Member States, plus an option of a further 100 million doses. This could be the biggest contract ever approved after the announcement of Phase III interim results.
The BioNTech/Pfizer vaccine must be stored at -70º C (-94º F) and will be sold at an amount that exceeds the manufacturing cost ($39 for a two-dose treatment). In the future, cheaper and more convenient vaccines (storable at higher temperatures) than the BioNTech/Pfizer vaccine are needed. AstraZeneca could take the first step in the right direction if their candidate vaccine is proven to be safe and effective. The company would sell it to the British government at no profit.
* * *
Advanced SARS-CoV-2 Candidates
Published 1 November
The development of SARS-CoV-2 vaccines will one day be recorded as one of the greatest research efforts in science. Never before have so many vaccines moved so quickly into trials for one disease (Dagotto 2020). More people will be able to get vaccinated more quickly than ever before.
An ideal pandemic vaccine would be acceptably safe for everyone, effective in inducing a durable protective immune response, rapidly scalable, stable at room temperature, single dose and cost effective (Bingham 2020). The current situation:
- On 1 November 2020, 10 SARS-CoV-2 vaccines had reached Phase III development (Table 1 and page 208). The first preliminary trial results are expected soon.
- So far, no vaccine has been approved after thorough clinical testing. (The “approvals” in Russia and China do not meet state-of-the-art approval criteria after thorough safety and efficacy testing.)
- If a vaccine is shown to be both effective and safe, it will first be offered to risk groups and essential professionals (medical staff, elderly people, police, fire fighters, etc.)
- Massive nationwide vaccine campaigns will not be available until well into 2021.
- Massive global vaccine campaigns are unlikely to have a more than marginal impact on the SARS-CoV-2 pandemic before 2022, if ever.
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Data from Phase II trials show that adverse effects, although generally not severe, are nonetheless frequent (rule of thumb: 50%) – pain at injection site, hyperthermia, headache, asthenia, muscle and joint pain (Folegatti 2020, Zhu 2020, Jackson 2020, Mulligan 2020, Logunov 2020). The “Big Three” vaccines in Phase III for which results are expected within the next months are:
- BNT162b2 (BioNTech/Pfizer/Fosun)
- ChAdOx1 (University of Oxford/AstraZeneca)
- mRNA-1273 (Moderna/NIH)
|Table 1. Vaccines in Phase III trials*|
|Developer||Candidate vaccine||Vaccine platform||Reference||News release|
|AstraZeneca / Oxford University
|Non-replicating vector||Folegatti 2020||28 June ‘20|
|Pfizer / BioNTech / Fosun (NCT04368728)||BNT162b1||RNA||Mulligan 2020||27 July ‘20|
|Moderna / NIAID (NCT04283461)||mRNA-1273||RNA||Jackson 2020||27 July ‘20|
|Sinovac Biotech (NCT04352608)||CoronaVac||Inactivated||Gao 2020||6 July ‘20|
|CanSino Biologics / Beijing Institute of Biotechnology (NCT04341389)||CTII-nCoV
|Replication-incompetent vector||Zhu 2020|
|Wuhan Institute of Biological Products / Sinopharm (ChiCTR2000031809)||Inactivated||Xia S 2020|
|Beijing Institute of Biological Products / Sinopharm||Inactivated|
|NVX-CoV2373||Replication-incompetent vector||Keech 2020||2 Sep ‘20|
|Janssen (Johnson & Johnson; NCT04505722)||Ad26.COV2.S||Mercado 2020||NYTimes
17 July ‘20
|Gamaleya Research Institute (NCT04530396)||Sputnik V||Replication-incompetent vector||Logunov 2020, Bucci 2020||NYTimes
11 August ‘20
* In Phase III trials, a vaccine is given to tens of thousands of people (50% will receive the true vaccine, 50% will receive a placebo injection) in order to show efficacy and reveal evidence of relatively rare side effects that might have been missed in earlier studies. The FDA expects that an acceptable COVID-19 vaccine would prevent disease or decrease its severity in at least 50% of people who are vaccinated (FDA 20200630).
The questions which are currently being addressed in Phase III vaccine trials have been summarized by Naor Bar-Zeev and William Moss (Bar-Zeev 2020):
- Will a single dose be sufficient in older adults, or is a booster dose required?
- Does longevity of response or rates of waning differ with a two-dose regimen, and does longevity of clinical protection require cell-mediated responses?
- Are there host-specific differences in immunogenicity by age, sex, or ethnicity?
- Do T cell responses correlate with protection irrespective of antibody titers?
- Are there specific adverse events in pregnant women?
After the beginning of mass vaccinations, more questions will arise:
- How will risk groups fare (e.g. elderly people with hypertension, diabetes, obesity, etc.)?
- Are re-vaccinations needed at regular intervals?
- Will SARS-CoV-2 mutate so that the vaccines will have to be adapted like the annual flu vaccines?
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As of 1 November 2020, no vaccine had been approved after thorough safety and efficacy testing.
WHO recommends that successful vaccines should show an estimated risk reduction of at least one-half (WHO 20200409). Well aware of the fact that rushing an ineffective or unsafe vaccine to the market could do substantial damage to people and their reputation, on 8 September 2020, nine pharmaceutical companies (AstraZeneca, BioNTech, Pfizer, Moderna, GlaxoSmithKline, Johnson & Johnson, Merck, Novavax and Sanofi) issued a joint pledge that they would “stand with science” and not put forward a vaccine until it had been thoroughly vetted for safety and efficacy (Thomas 2020).
Humane challenge studies
Human challenge studies (HCS) could assess the effectiveness of experimental vaccines more rapidly and thereby accelerate vaccine development. The prospect of deliberately infecting young adults — even those at low risk of severe disease — with SARS-CoV-2, a deadly pathogen that has few proven treatments, is uncharted medical and bioethical territory (Callaway 2020, Deming 2020). Typically, undertaking human challenge studies in vaccine development requires that the disease for which a challenge would be introduced either has an available rescue therapy to treat those who become infected or the disease is known to be self-limiting (Kahn 2020).
In the UK, the first COVID-19 human challenge studies could begin in January 2021. The first phase aims to discover the smallest amount of virus it takes to cause the infection in up to 90 healthy young people, aged between 18 and 30 years, who are at the lowest risk of harm from COVID-19 (Kirky 2020, Cookson 2020).
WHO has published criteria for the ethical acceptability of COVID-19 human challenge studies (WHO 20200506). An ethical study design would involve healthy participants in inpatient settings with immediate access to high-quality health care and strict infection control measures (Jamrozik 2020). Some authors argue that human challenge studies face unacceptable ethics challenges, and, further, undertaking them would do a disservice to the public by undermining already strained confidence in the vaccine development process (Kahn 2020). If the studies procede, it will be interesting to understand the relationship between efficacy data from human challenge studies in young individuals and protection of the elderly – the population which is at highest risk from SARS-CoV-2 infection (Hodgson 2020).
Vaccine development is fraught with obstacles. As demonstrated by the ChAdOx1 experience (Oxford/AstraZeneca), serious adverse events can at any time grind a trial to a halt (Phillips 2020). Should a tranverse myelitis (Shah 2020) be recognized as triggered by the vaccine, the trial would be stopped immediately. Vaccine-related adverse events, either debilitating or fatal, might even be recognized years after approval and lead to the withdrawel of the vaccine. Both the public and vaccine developers should be prepared for unanticipated turns in the COVID Vaccine Saga. There is a piece of good news, though: the D614G mutation of the SARS-CoV-2 spike protein does not seem to affect adversely the efficacy of vaccines (McAuley 2020).
Access to a safe vaccine might be unequal, both within countries and between them. Within countries, health authorities will prepare strategic prioritization plans (Lipsitch 2020). Vaccines will be offered first to healthcare workers; then to people at high risk of severe COVID-19 and maybe those living in epidemiological hotspots; and, finally, to the rest of the population – if they want to get vaccinated (Schwartz 2020, Bingham 2020). Between countries, there is no doubt that those that produce vaccines will get the vaccine before countries that don’t. On 24 August 2020, wealthy countries had pre-ordered around two billion vaccine doses without knowing which one may prove effective (see an overview of the August situation in Callaway 2020). However, it is not acceptable that low-risk people in wealthy countries get the vaccine while health care workers in low- and middle-income countries do not. To avoid such a scenario, GAVI, the Vaccine Alliance (a Geneva-based funder of vaccines for low-income countries), the Coalition for Epidemic Preparedness Innovation (CEPI) and the World Health Organization have set up the COVID-19 Vaccines Global Access (COVAX) Facility (Kupferschmidt 2020, Jeyanathan 2020). COVAX aims to accelerate the development and manufacture of COVID-19 vaccines, and to guarantee fair and equitable access for every country in the world by securing 2 billion vaccine doses. One billion have already been reserved for 92 low- and middle-income countries and economies (LMICS), which make up half the world’s population.
Impact of vaccines on the pandemic
A vaccine against SARS-CoV-2 might act against infection, disease, or transmission and a vaccine capable of reducing any of these elements could contribute to disease control (Hodgson 2020). It is too early to predict if SARS-CoV-2 vaccines will have a measurable impact on the course of the SARS-CoV-2 pandemic over the coming years.
Vaccines in Phase III
ChAdOx1, developed by the University of Oxford, AstraZeneca and the Serum Institute of India, uses replication-deficient simian adenovirus vector ChAdOx1 which contains the full-length, unmodified structural surface glycoprotein (spike protein) of SARS-CoV-2. Results from a Phase I/II randomized trial showed that in ChAdOx1 vaccinees, T cell responses peaked on day 14, anti-spike IgG responses rose by day 28, and neutralizing antibody responses against SARS-CoV-2 were detected in > 90%. Adverse events such as fatigue, headache, and local tenderness commonly occurred, but there were no serious adverse events (Folegatti 2020).
BNT162b1, developed by BioNTech, Pfizer and Fosun, is a lipid nanoparticle-formulated, nucleoside-modified mRNA vaccine that encodes trimerized SARS-CoV-2 spike glycoprotein receptor-binding domain. Early studies indicated that well-tolerated dose levels of BNT162b1 efficiently elicited high titer, broad serum neutralizing responses, Th1 phenotype CD4+ T helper cell responses, and strong interferon γ and interleukin-2 producing CD8+ cytotoxic T-cell responses (Sahin 2020, Mulligan 2020). On 27 July, the companies announced a Phase II/III trial with 30,000 volunteers in the US, Germany, Argentina, and Brazil, among others. If the clinical studies are successful, BioNTech and Pfizer want to apply for approval of the vaccine as early as this year. If approved, BioNTech, Pfizer and Fosun could manufacture up to 100 million vaccine doses by the end of 2020 and over 1.3 billion by the end of 2021.
mRNA-1273, developed by Moderna, is a lipid nanoparticle–encapsulated, nucleoside-modified messenger RNA (mRNA)–based vaccine that encodes the SARS-CoV-2 spike (S) glycoprotein stabilized in its prefusion conformation. mRNA-1273 induced potent neutralizing antibody responses to both wild type (D614) and D614G mutant2 SARS-CoV-2 as well as CD8+ T cell responses, and protects against SARS-CoV-2 infection in mice (Corbett 2020) and non-human primates (Corbett 2020b). In early clinical trials, it induced anti–SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified (Jackson 2020). The Phase III trial, launched on 27 July 2020, will enroll 30,000 healthy people in the US.
CoronaVac© is an inactivated virus vaccine developed by Sinovac Biotech, Ltd. In macaques, the vaccine provided partial or complete protection against a SARS-CoV-2 challenge (Gao 2020). In September 2020, the company reported data from healthy adults aged 60 years and above in Phase I/II clinical trials where the seroconversion rate for elderly participants would have been comparable to that in a group of 18 to 59 years healthy people. The data have not yet been published in a peer-reviewed journal. Phase III trials enrolled 24,000 people in Brazil, Indonesia and Turkey. Enrolment of children younger than 18 started in September 2020. The company is planning to produce 300 million vaccine doses in 2021.
CTII-nCoV, developed by CanSino Biologics in partnership with the Institute of Biology at the Chinese Academy of Military Medical Sciences, is based on an adenovirus called Ad5. Results from Phase II trials demonstrated that the vaccine produced significant neutralizing antibody responses to live SARS-CoV-2 (Zhu 2020). In a Phase II trial, a single injection of the Ad5-vectored COVID-19 vaccine at 1 × 1011 viral particles and 5 × 1010 viral particles induced comparable specific immune responses to the spike glycoprotein at day 28. Positive specific T cell responses were found in 90% and 88% of participants receiving the vaccine at 1 × 1011 and 5 × 1010 viral particles, respectively. 95% of participants in the 1 × 1011 viral particles dose group and 91% of the recipients in the 5 × 1010 viral particles dose group showed either cellular or humoral immune responses at day 28 post- vaccination (Zhu 2020). The authors found that compared with the younger population, older people had a significantly lower immune response, but higher tolerability, to the Ad5-vector COVID-19 vaccine. Pre-existing immunity to the Ad5 vector and increasing age could partially hamper the specific immune responses to vaccination, particularly for the humoral immune responses. Adverse events such as fever, fatigue, headache, or local site pain were comparable to the ChAdOx1 study above.
On 25 June, the Chinese military approved the vaccine for a year as a “specially needed drug.” CanSino would not say whether vaccination was to be mandatory or optional for soldiers.
Wuhan Institute vaccine
An inactivated virus vaccine developed by the Wuhan Institute of Biological Products, put into clinical trials by the state-owned Chinese company Sinopharm, showed that the vaccine produced antibodies in volunteers (Xia S 2020). Some volunteers experienced fevers and other side effects. Phase III trials are under way in China, Peru, Morocco and the United Arab Emirates.
Beijing Institute vaccine
Another inactivated virus vaccine developed by the Beijing Institute of Biological Products (again put into clinical trials by Sinopharm), is currently being tested in Phase III trials in China and in the United Arab Emirates.
NVX-CoV2373, developed by Novavax, is a recombinant nanoparticle vaccine (rSARS-CoV-2) composed of trimeric full-length SARS-CoV-2 spike glycoproteins and Matrix-M1 adjuvant (Keech 2020). In a Phase I/II trial, the vaccine induced levels of neutralizing antibodies that closely correlated with anti-spike IgG. After the second vaccination neutralizing antibody responses exceeded values seen in symptomatic COVID-19 outpatients and were of the magnitude seen in convalescent serum from hospitalized patients with COVID-19.
Ad26.COV2.S, developed by Janssen, is a recombinant replication-incompetent adenovirus type 26 (Ad26) vector-based COVID-19 vaccine encoding a prefusion-stabilized SARS-CoV-2 Spike immunogen. Its potency in eliciting protective immunity against SARS-CoV-2 infection was successfully demonstrated in a non-human primate challenge model (Mercado 2020). Ad26.COV2.S induced robust neutralizing antibody responses and provided complete protection against a SARS-CoV-2 challenge in five out of six rhesus macaques and near-complete protection in one out of six macaques (Mercado 2020). The vaccine platform for the development of this optimized S protein-based vaccine has been recently described (Bos 2020). A Phase III study plans to enrol up to 60,000 participants.
Sputnik V (formerly Gam-COVID-Vac Lyo), developed by the Gamaleya Research Institute, is a combination of two adenoviruses, Ad5 and Ad26, each carrying an S antigen of the new coronavirus. Phase III trials, initially planned for just 2,000 volunteers, were expanded to 40,000.
The SARS-CoV-2 pandemic and the unprecedented research effort to develop multiple vaccines on different platforms is a good occasion to recall some immunization fundamentals. Recovery from infections often induces long-term and sometimes life-long immunity against the causative pathogen. After the resolution of the infection, immunological memory protects against re-infection and is mediated by specific antibodies and T-cells.
In contrast, immunizations confer immunity without exposure to virulent pathogens. Immunization can be passive or active. In passive immunisation protective antibodies are transfered from a donor into a recipient whereas active immunization induces a protective immune response in the recipient.
Passive immunization against SARS-CoV-2
Passive immunization against SARS-CoV-2 can be achieved with convalescent plasma or with neutralizing monoclonal antibodies.
Treatment with human convalescent plasma (CP) is based on the assumption that protective antibodies against the causative pathogen are present in the blood of people who have overcome an infectious disease. For example, CP has been used to treat some infectious diseases such as Argentine hemorrhagic fever (Casadevall 2004). CP was also used to treat SARS patients in the 2002/2003 epidemic but not in controlled clinical studies; a later meta-analysis concluded that the treatment was probably safe and perhaps helpful (Mair-Jenkins 2015).
CP could become an option for prevention and treatment of COVID-19 disease when there are sufficient numbers of people who have recovered and can donate immunoglobulin-containing serum (Casadevall 2020). Antibodies that are found in CP are very stable. Pathogen inactivation (using psoralen and UV light) did not impair the stability and neutralizing capacity of SARS-CoV-2-specific antibodies that was also preserved at 100% when the plasma was shock frozen at −30°C after pathogen-inactivation or stored as liquid plasma for up to 9 days (Tonn 2020). However, in a recently published open label randomized controlled trial (the largest to date with results) 464 patients were assigned either to two doses of 200 mL CP or best standard of care only. The result was sobering: progression to severe disease or all-cause mortality at 28 days after enrolment occurred in 44 (19%) participants in the CP arm and 41 (18%) in the control arm (Agarwal 2020).
The major caveat of CP is quantity and quality of antibody titers. In plasma from 149 patients collected on average 39 days after the onset of symptoms, neutralizing titers were extremely variable. Most plasmas did not contain high levels of neutralizing activity (Robbiani 2020). There seems to be a correlation between serum neutralizing capacity and disease severity, suggesting that the collection of CP should be restricted to those with more severe symptoms (Chen 2020). Another, unintended, consequence of receiving CP may be that recipients will not develop their own immunity, putting them at risk for re-infection.
In addition, in light of the possibility of antibody-dependent disease enhancement (ADE), safety is still a hypothetical consideration in the ongoing CP trials. One study on macaques found that passive transfer of anti-SARS-CoV-S immunoglobulin from immunized monkeys into naïve recipients resulted in acute lung injury after infection. The proposed mechanism was a diversion of macrophage activation from wound healing to pro-inflammatory (Liu 2019). Enhanced lung-pathology upon antibody-transfer was also observed in a rabbit model of MERS (Houser 2017). Convalescent plasma has been given to MERS patients and one case-report raises the possibility of acute lung Injury following convalescent plasma transfusion (Chun 2016).
The future development of anti-SARS-CoV-2 convalescent plasma should take into account 1) the potential harms of the non-immune components of convalescent plasma (especially prothrombotic risks); 2) that only donor plasma with detectable titers of neutralizing antibodies be given to trial participants; 3) ensure double blind designs with placebo controls as the gold standard for future trials; 4) preclude non-immune plasma as a control intervention, because of potential harms and availability of lower risk alternatives such as normal saline (Pathak 2020).
Find more information on CP in the Treatment chapter, page 344.
Competition is heating up to produce targeted monoclonal antibodies which could both prevent and treat COVID-19 (Cohen 2020). The development of highly successful monoclonal antibody-based therapies for cancer and immune disorders has created a wealth of expertise and manufacturing capabilities (Biopharma 2020) and neutralising monoclonal antibodies are now a plausible therapeutic option against infectious diseases (Marston 2018). Monoclonal antibodies against rabies virus and against the respiratory syncytial virus (RSV) are approved for the treatment of patients and other monoclonal antibodies are in advanced stages of clinical trials (Walker 2018). Both protective and pathogenic effects were observed (Wang Q 2016, Chen X 2020).
SARS-CoV-2 neutralizing human monoclonal antibodies were intensely studied in 2020 (Robbiani 2020, Wec 2020, Ju B 2020). It was shown that REGN-CoV-2, a cocktail of two antibodies, might preclude the appearance of escape mutants (Baum 2020) and decrease virus-induced pathological sequalae in rhesus macaques (Baum 2020b). In hamsters, the cocktail limited weight loss and evidence of pneumonia in the lungs. The first (not yet peer reviewed!) published clinical results of REGN-CoV-2 describe the results in non-hospitalized COVID-19 patients with symptom onset ≤ 7 days from randomization and not on any putative COVID-19 therapy. After single doses of REGN-CoV-2 at 2.4 g IV (lower dose), 8 g IV (higher dose) or placebo, the company found a reduction of “viral load” in nasopharyngeal (NP) swabs of -1.92 and -1.64 log10 copies/mL, compared to -1.41 with placebo (Regeneron 2020). These results are not particularly impressive.
The ‘COVID-19 antibodysphere’ features companies like Amgen, AstraZeneca, Vir, Regeneron, Lilly and Adagio (Biopharma 2020). However, the future role of monoclonal antibodies as a bridging solution before the general availability of vaccines and efficient antiviral drugs is unclear. These drugs are complex and expensive to produce, leaving people from poor countries locked out (Ledford 2020, Ledford 2020b) and fears have been voiced that they could split the world into the haves and have-nots, like many other drugs before (Cohen 2020). Fortunately, these fears may not materialize. As soon as the first truly effective antiviral drugs become available – as for HSV in 1981, HIV in 1996 and HCV in 2013 – there will be no need for monoclonal antibodies anymore.
Find more details on monoclonal antibodies in the Treatment chapter, page 340.
Active immunization against SARS-CoV-2
At the time of this writing (October 2020), there are more than 170 COVID-19 vaccine candidates in different stages of preclinical development. Ten candidate vaccines are in Phase III clinical trials (Thanh Le 2020). If one considers that the development of a vaccine usually takes well over 10 years to complete (Heaton 2020), it becomes clear how quickly progress is being made (Slaoui 2020).
This rapid development is based on a massive global effort, including the parallelization of development and production steps that have traditionally been carried out sequentially (Lurie 2020), the knowledge generated in attempts to develop vaccines against SARS-CoV-1 and MERS-CoV, and innovative techniques (Hekele 2013) that were not available until recently. The speed of SARS-CoV-2 vaccine development is breathtaking. On 11 January 2020 Chinese researches published the sequence of the SARS-CoV-2 genome on the internet. Approximately 2 months later, on 16 March, an mRNA-based vaccine entered a Phase I clinical trial (Arnold 2020).
Earlier work had identified the S protein of SARS-CoV and MERS-CoV as a suitable vaccine target. The S protein binds to its cellular receptor, ACE2, to infect human cells. With the sequencing of the genome of SARS-CoV-2, the high homology between the S proteins of the 3 viruses was known and a little later the interaction of SARS-CoV-2 with ACE was confirmed (Hoffmann 2020). A relevant target structure for immune responses was identified in record time.
However, there are still some hurdles to overcome in vaccine development. This includes the fact that the correlates of protective immunity against SARS-CoV-2 are currently incompletely understood, that the available data indicate that immunity against SARS-CoV-2 may not be very long-lasting and that preclinical studies on vaccine candidates against SARS-CoV and MERS-CoV have given indications of possible side effects (see below).
SARS-CoV-2 vaccine platforms
The platforms used for SARS-CoV-2 vaccine developments have recently been summarized in an excellent review by Florian Krammer (Krammer 2020). Current SARS-CoV-2 vaccine candidates include (the letters in the brackets refer to Figure 3 of the Krammer review):
- inactivated virus vaccines (c)
- live attenuated vaccines (d)
- recombinant protein vaccines based on the spike protein (e), the RBD (f) or on virus-like particles (g)
- replication-incompetent vector vaccines (h)
- replication-competent vector vaccines (i)
- inactivated virus vector vaccines that display the spike protein on their surface (j)
- DNA vaccines (k)
- RNA vaccines (l)
The most traditional way to produce vaccines is the use of whole viruses, which are either attenuated or inactivated. Currently licensed examples include the vaccines against measles and yellow fever (attenuated virus) and influenza and polio (inactivated viruses). Two inactivated vaccines protect rhesus monkeys from SARS-CoV-2. The vaccines were well tolerated preclinically; in particular, no type 2 immunopathology was found in the lungs (see below: pathological immune responses) (Gao Q 2020, Wang H 2020). Various vaccines that use inactivated SARS-CoV-2 as an immunogen are currently available in different phases of clinical trials, three of which are already in Phase III studies (WHO Landscape 2020).
Another approach is to use recombinant viral proteins as vaccine; licensed examples include the vaccines against hepatitis B and human papilloma virus. Efforts are ongoing to develop recombinant SARS-CoV-2 S protein as an immunogen. Nine vaccines that use recombinant SARS-CoV-2 S protein as an immunogen are in the early phases of clinical trials (Phase I or I/II) (WHO Landscape 2020).
A more recent approach is to use recombinant viral vectors in which a relevant antigen of the pathogenic virus is expressed.
Currently, the Ebola vaccine is the only approved vaccine based on this principle (Henao-Restrepo 2017). A recombinant vaccine protected rhesus monkeys from SARS-CoV-2. The vaccine was well tolerated; in particular, no type 2 immunopathology was found in the lungs (see below: pathological immune responses) (van Doremalen 2020). Three different adenovirus-based recombinant vaccines against SARS-CoV-2 are currently in clinical Phase III studies (WHO Landscape 2020). A potential problem with these vaccines could be pre-existing immune responses of the vaccinees against adenoviruses (Zhu FC 2020).
Four DNA vaccines against SARS-CoV-2 are currently in the early phases of clinical trials (Phase I or I/II) (WHO Landscape 2020). There are currently no approved DNA vaccines, which could make the approval process more complicated compared to other vaccines.
An mRNA vaccine intended to induce immune responses against SARS-CoV-2 was already tested in a clinical Phase I study in March 2020 (Jackson 2020). Two mRNA vaccines are currently in Phase III clinical trials, another is in a Phase II trial, and others are in earlier phases of clinical trials (WHO Landscape 2020). The approval process for RNA vaccines could be more complicated than for conventional vaccines because currently there are no approved mRNA vaccines for any indication.
Issues to address during vaccine development
Vaccines against coronaviruses can induce pathological immune responses.
Rarely, vaccines can enhance disease rather than protect from disease (Kim 1969, Openshaw 2001). Some vaccine candidates against SARS-CoV-1 or MERS-CoV have caused disease-intensifying immunopathological effects in some pre-clinical models. The safety of a vaccine against SARS-CoV-2 is of course of essential importance (Lambert 2020).
Immunization with recombinant SARS-CoV spike (S) -coding modified vaccinia virus Ankara (rMVA) causes hepatitis in ferrets.
Ferrets are susceptible to SARS-CoV and SARS-CoV-2 infections (Kim YI 2020). Weingartl et al. immunized ferrets with a recombinant modified vaccinia virus Ankara (rMVA), which encoded the SARS-CoV S protein (Weingartl 2004). After infection with the virus, high titers of neutralizing antibodies were detectable in the immunized animals. Nevertheless, the immunized infected ferrets developed severe hepatitis while the non-immunized did not (Weingartl 2004).
Type 2 immunopathology in the lungs of immunized mice
Bolles et al. (Bolles 2011) immunized mice with inactivated SARS-CoV with or without adjuvant. The vaccine protected young and old animals from morbidity and mortality after infection with high doses of virus. If the mice were infected with a heterologous virus strain, the immunized animals developed more pronounced inflammatory infiltrates and pulmonary eosinophilia than the non-immunized (Bolles 2011). These results were later confirmed by another working group (Tseng CT 2012). Eosinophilic lung infiltrates were also observed in mice after immunization with a recombinant baculovirus (S protein) or coronavirus-like particles (VLPs) that expressed SARS-CoV S protein. It is important to note that these are histopathological findings; the immunized mice still had reduced virus titers after infection (Tseng CT 2012, Lokugamage 2008). Nevertheless, the findings are worrying. They are similar to the histopathological changes seen in the 1960s in children who became ill after immunization with a vaccine against RSV (Castilow 2007). Pathological changes in the lungs and even pneumonia after infection with SARS-CoV were also observed in mice in other SARS-CoV vaccine candidates (Yasui 2008).
Similar findings have been reported for vaccine candidates for MERS-CoV. An inactivated MERS-CoV vaccine induced neutralizing antibodies in mice. Nevertheless, after infection, the immunized mice developed an increased type 2 pathology in the lungs with increased eosinophilic infiltrates and increased concentrations of IL-5 and IL-13 (Agrawal 2016). Recent studies suggest that the development of type 2 immunopathology can be influenced by the choice of appropriate adjuvants, e.g. TLR ligands, for inactivated viruses, or recombinant S protein can be avoided (Iwata-Yoshikawa 2014, Honda-Okubo 2015).
Overall, these findings are a clear indication that during the preclinical development of vaccines against SARS-CoV-2, an intensive search should be made for immunopathological changes in the lungs of the immunized animals. It is encouraging that many of the pre-clinical studies published to date on SARS-CoV-2 vaccine candidates explicitly indicate that such changes have been sought and not found.
Type 2 immunopathology in the lungs of immunized primates
In a recent study Chinese macaques were vaccinated with a modified vaccinia Ankara (MVA) virus encoding full-length SARS-CoV S glycoprotein (ADS-MVA) and challenged with SARS-CoV 8 weeks later (Liu 2019). Vaccination induced high levels of antibodies and reduced virus loads. However, the vaccinated monkeys had diffuse alveolar damage (DAD) (Liu 2019). These findings are similar to those of an earlier study in which macaques were immunized with inactivated SARS-CoV. Three monkeys were protected upon challenge whereas one macaque had lung pathology consistent with antibody-dependent disease enhancement (ADE) (Wang 2016). The authors suspect that only antibodies against certain SARS-CoV S epitopes induce the immunopathology. In the previously published SARS-CoV-2 vaccination studies in monkeys, no lung pathology was observed (Gao Q 2020, Wang H 2020, van Doremalen 2020). Overall, there is no evidence of immunopathology after vaccination and infection in the preclinical studies published to date.
The diverse and massive efforts in vaccine development and the unprecedented pace of progress give rise to hope that an effective and safe vaccine will soon be available. However, some important questions remain unanswered.
Correlates of Protection
Knowledge about the immune responses against SARS-CoV-2 is growing rapidly (Vabret 2020); it seems clear that neutralizing antibodies against the S protein can mediate protection. SARS-CoV-2-specific T cells can also be present in people without detectable antibodies against SARS-CoV-2 (Braun 2020, Grifoni 2020, Sekine 2020). Preclinical studies on SARS (Li CK 2008) and MERS (Zhao J 2017) suggest that virus-specific CD4+ (Zhao J 2016) and CD8+ (Channappanavar 2014) T cells can be protective even in the absence of serologically detectable antibodies (Tang F 2011).
Longevity of the immunological memory against SARS-CoV-2
Ideally, a vaccine induces long-term immunity; unfortunately, this goal may not be realistic for SARS-CoV-2. Infections with common cold coronaviruses generate only a short-lived immunity. Experiments from the 1980s have shown that just one year after inoculation with coronavirus 229E, the majority of the test subjects could be infected again. They did have milder symptoms than non-inoculated subjects, so a certain protection was seen despite renewed infection (Callow 1990).
Experiences from the 2002-2004 SARS-CoV outbreak, too, suggest that SARS-CoV-2 immune responses will be short-lived. Six years after having suffered SARS disease, antibodies to SARS-CoV were no longer detectable in 21/23 patients (Tang F 2011). In contrast, SARS-CoV-specific T cells were still detectable, which suggests the possibility that T cell memory against corona viruses may be more long-lasting than serological memory (Tang F 2011). Similar findings have been described for the immune response after MERS disease (Zhao J 2017); however, there is currently no reliable knowledge about the longevity of T cell memory against SARS-CoV 2. There have been reports of renewed SARS-CoV-2 infections after surviving the first infection (To KK 2020).
After almost one year of research, the picture of immunological memory against SARS-CoV-2 is becoming clearer. The kinetics of the neutralizing antibody response to SARS-CoV-2 is typical of an acute viral infection where a peak response is detected 3–4 weeks post-infection, which then wanes (Seow 2020). More than 90% of of infected individuals with mild-to-moderate COVID-19 experience might develop robust IgG antibody responses against the viral spike protein and titers will be relatively stable for months Anti-spike binding titers correlate with neutralization of authentic SARS-CoV-2 (Gudbjartsson 2020, Wajnberg 2020, Alter 2020). Patients with a worse clinical classification may have higher neutralizing antibody titer (Wang X 2020).
However, asymptomatic individuals have a weaker immune response to SARS-CoV-2 infection than patients with severe COVID-19 (Long QX 2020) and humoral immunity against SARS-CoV-2 may not be long lasting in this large group that composes the majority of infected persons (Ibarrondo 2020, Weis 2020). One group showed that in individuals who develop a low neutralizing antibody response (ID50 100–300), titers can return to baseline over a relatively short period, whereas those who develop a robust neutralizing antibody response maintain titers > 1,000 despite the initial decline (Seow 2020).
Pre-existing immune responses against SARS-CoV-2
SARS-CoV-2-specific CD4+ and CD8+ T lymphocytes can be detected in around 20 to 100% of non-exposed healthy volunteers (Braun 2020, Grifoni 2020, Mateus 2020, Bacher 2020). It has been speculated that these cross-reactive T lymphocytes could be protective against SARS-CoV-2 or influence the course of the disease. As a matter of fact, it is known that cross-reactive T cells can influence the course of viral infections both positively and negatively (Ngono 2018). Antibodies that neutralize SARS-CoV-2 have also been detected in uninfected and non-exposed healthy volunteers (Ng KW 2020).
We might not rely on protection without exposure, though. In a recently published pre-print study from Rockefeller University, the authors measured neutralizing activity against SARS-CoV-2 in pre-pandemic sera from patients with prior PCR-confirmed seasonal coronavirus infection. While neutralizing activity against seasonal coronaviruses was detected in nearly all sera, cross-reactive neutralizing activity against SARS-CoV-2 was undetectable (Posten 2020). The authors conclude that while it is possible that there are rare instances of individuals possessing antibodies from prior seasonal HCoV infection who may be able to also target SARS-CoV-2 S, their data would argue against a broad role for pre-existing protective humoral immunity against SARS-CoV-2.
Recently, a provocative concept was introduced by Alexander Scheffold and colleagues. The authors propose the immunological age as an independent risk factor to develop severe COVID-19 (Bacher 2020). Their reasoning:
- Unexposed individuals harbor SARS-CoV-2-specific memory T cells with marginal cross-reactivity to common cold corona and other unrelated viruses.
- These T cells display low functional avidity and broad protein target specificities and their frequencies correlate with the overall size of the CD4+ memory compartment reflecting the immunological age of an individual.
- COVID-19 patients generate strong pro-inflammatory T cells responses, that increase with disease severity.
- Unexpectedly, severe disease is associated with lower functional avidity and TCR clonality.
- Low avidity pre-existing T cell memory negatively impacts on the T cell response against neoantigens such as SARS-CoV-2, which may predispose to develop inappropriate immune reactions especially in the elderly.
Find more about this topic in the 6th edition of COVID Reference.
Vaccines are the most potent medical products of all times to prevent morbidity and mortality. Over the last two centuries, no other medical intervention has saved as many lives. Without vaccines, many of today’s anti-vaccine activists (Burki 2020) would not have been born (and maybe neither you nor me) because of lack of ancestors – one or more of them would have succumbed to infectious disease before reaching mating age. Vaccines train the body’s immune system to recognize and fight pathogens and on the next exposure to the pathogen, the immune system is ready to fight the invader off. The vaccination procedure is simple: introduce certain molecules from the pathogen into the body and trigger an immune response. Vaccines are ‘elegant medicine’ – they prevent rather than treat a disease.
At the end of this COVID Year One, virology, biologic chemistry and immunology are the celebrated fields of medicine. Virology explores the structure and functioning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and, together with biologic chemistry, prepares the terrain for future drug development. In the meantime, immunology explores the virus-human interface and describes how the human body fights back and forms a memory after the first encounter with SARS-CoV-2: it examines why most people recover from the infection while a few die and other remain disabled; and it contributes to the understanding of the biological mechanisms that lead to illness and death. Why do older people die from coronavirus disease 2019 (COVID-19) while younger people don’t? Why are people with hypertension, diabetes or obesity at increased risk of severe COVID-19? Immunology also tries to elucidate the mystery of superspreader individuals, those few acutely SARS-CoV-2 infected people who are thought to be responsible for the vast majority of transmissions. Finally, immunology will spin out the most powerful antiviral weapon: vaccines.
One challenge for the developers of COVID-19 vaccine(s) is that the elderly are most susceptible to the infection and carry a particularly high risk for severe or lethal disease. Due to immunosenescence, the elderly are notoriously difficult to immunize, requiring higher doses or particular immunization schemes in order to generate a protective immune response. Studies in mice indicate that older animals are also more likely to develop immunopathology upon vaccination.
The SARS-CoV-2 pandemic is a colossal challenge for healthcare systems and societies. It is also the time of the ‘Great Rehearsal’. By coordinating global resources and supra-national structures to react swiftly, science is currently creating the infrastructure to fight any other new and potentially far deadlier viral disease that emerges in the future. SARS-CoV-2 is not the last pathogen humanity will have to deal with in the 21st century and more enzootic viruses will jump from their animal reservoirs to humans. However, after this pandemic, hopefully we will be better prepared for future challenges, with new vaccine platforms that can quickly be adapted to newly emerging viral diseases. There is even a final twist to the unexpected events of 2020: the SARS-CoV-2 pandemic is opening up a new era of vaccine development. In 10 years we can expect to have a wide range of new and innovative vaccines we would not have dared to previously dream of.
 The Coalition for Epidemic Preparedness Innovation (CEPI), an international nongovernmental organization funded by the Wellcome Trust, the Bill and Melinda Gates Foundation, the European Commission, and eight countries (Australia, Belgium, Canada, Ethiopia, Germany, Japan, Norway, and the United Kingdom), is supporting development of vaccines against five epidemic pathogens on the World Health Organization (WHO) priority list (Lurie 2020).
 mRNA vaccines: Two mRNA vaccine formulations against COVID-19 have now been tested in tens of thousands of volunteers: one developed by a collaboration between Pfizer and BioNTech, and the other by Moderna and the National Institute of Allergy and Infectious Diseases (NIAID) in the US (Nat Biomed Eng 2020). mRNA vaccines like BNT162b2 have the potential to be truly transformative but have never been tested in large-scale human trials; see Abbasi 2020 for a tour of mRNA vaccines today and beyond COVID-19. BioNTech, Moderna, CureVac and GSK own nearly half of the mRNA vaccine patent applications (Martin 2020).
By Thomas Kamradt &