Rapid progress is being made in deciphering the immune responses to SARS-CoV-2. Nevertheless, some of the important and most urgent questions remain unanswered including:
- Is someone who has recovers from COVID-19 protected from the disease?
- If yes, how long does the immune protection last?
- What are the correlates of protection?
- Why is the disease so much more severe in the elderly?
- How does the immune response against SARS-CoV-2 contribute to disease development? Are there pathogenic immune responses?
- Can we use immunological parameters to predict an individual patient’s risk in developing severe disease?
- Can we develop a vaccine against SARS-CoV-2?
The current state of knowledge is beautifully summarised in a recent extensive review (Vabret 2020).
In the absence of robust experimental or clinical data on SARS-CoV-2-induced immune responses we can make some educated guesses based on prior experiences with endemic coronaviruses (e.g. 229E or OC43), the SARS-CoV and the MERS-CoV viruses. Experimental, serological and sero-epidemiological studies strongly suggest that coronaviruses, including SARS-CoV-2 induce neutralizing and protective antibodies. These studies also seem to indicate that antibody-mediated protection is short-lived.
Less is known about cellular immune responses, i.e. T cell responses against coronaviruses. Experimental evidence from studies in mice suggests that T cells residing in the mucosa of the respiratory tract could be an important correlate of protection. However, although mice can be infected with coronaviruses including SARS-CoV, they do not develop the severe pulmonary symptoms that are characteristic of SARS and COVID-19. Therefore, these results have to be interpreted with caution. Human T cells from the respiratory mucosa of ill recovering humans would be necessary to clarify the issue but are difficult to come by.
These questions are not simply of an academic nature. Rational vaccine design is based on solid knowledge about protective immunity. As long as we do not know which protective immune response we need to induce by vaccination, vaccine development remains guesswork.
Important insights come from two recent studies on T cell responses against SARS-CoV-2 in healthy donors and COVID-19 patients. Alessandro Sette and coworkers examined T cell responses in COVID-19 patients and 11 healthy controls (Grifoni 2020). Using a pool of peptides from the SARS-CoV-2 S-, M-, N- and nsp proteins, they detected CD4+ and CD8+ T cell responses in 100% and 80% of the patients, respectively. Perhaps more surprisingly they also found reactive CD4+ and CD8+ T cells in 50% and 20% of unexposed healthy donors. In a similar study, Andreas Thiel and co-workers used large pools of overlapping peptides spanning the entire sequence of the SARS-CoV-2 S protein and detected S-reactive CD4+ T cells in 83% of the COVID-19 patients and 34% of the seronegative healthy donors (Braun 2020). The high percentage of seronegative healthy donors who have SARS-CoV-2 reactive T cells is explained by previous exposure to other coronaviruses (“common cold” coronaviruses) which have proteins that are highly similar to those of SARS-CoV-2. Thiel and coworkers went on to show that T cells targeting the C-terminus of the S protein occur frequently in both patients and healthy donors, indicating cross-reactivity, whereas T cells targeting the N-terminus occur frequently in patients but not in healthy donors. The important question posed by these results is whether those frequently occuring cross-reactive T cells in healthy donors confer some degree of protection, are inconsequential or even potentially harmful if someone who possesses these cells becomes infected with SARS-CoV-2. Longitudinal studies will be needed to provide the answer and to determine how long after infection the SARS-CoV-2-specific T cells remain detectable in the blood of patients who have recovered from the disease.
- Recovery from infection often induces long-term and sometimes life-long immunity against the causative pathogen.
- Immunological memory protects against re-infection and is mediated by specific antibodies and T cells.
- Immunizations confer immunity without exposure to virulent pathogens. Immunization can be passive or active.
- In passive immunization protective antibodies are transferred from a donor to a recipient whereas active immunization induces a protective immune response in the recipient.
Passive immunization against SARS-CoV-2
Passive immunization against COVID-19 can be achieved with convalescent plasma, hyperimmune sera, or with neutralizing monoclonal antibodies.
Treatment of patients with convalescent plasma is based on the idea that someone who has recovered from an infection will have antibodies against the causative pathogen in their blood. Convalescent plasma is used for some infectious diseases including Argentinian hemorrhagic fever (Casadevall 2004). Prior experience shows antibody transfer is most effective when given prophylactically or early in the disease.
Convalescent plasma has been given to SARS patients. Regrettably, this was not done in the context of controlled clinical studies. A meta-analysis could therefore only conclude that the treatment was probably safe and perhaps helpful (Mair-Jenkins 2015). While drugs or vaccines against COVID-19 are still months or years away, convalescent plasma is available now.
To date, we do not know if all patients who have recovered from COVID-19 will harbor enough titers of neutralizing antibodies to confer protection upon transfer of plasma. Even the assays to determine the concentration of neutralizing antibodies are not standardized nor widely available.
Currently, convalescent plasma is given to COVID-19 patients (see Treatment chapter). Several randomized clinical studies are underway. The multicenter CONCOR-1 trial in Canada id due to start on April 27th with 1,200 participants planned and the CONCOVID trial in The Netherlands with a target number of more than 400 patients. These and similar studies will show if convalescent plasma is safe and effective.
Given the possibility of antibody-dependent disease enhancement (ADE), safety is an important consideration in these 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).
Taken together, these data stress the necessity to administer convalescent plasma in controlled trials, which will determine safety and efficacy.
Pooled immunoglobulin preparations
Hyperimmune globulin preparations, e.g. cytomegalovirus immunoglobulin (CMVIG), pooled from many different donors, are currently the most frequently used form of passive antibody transfer. These preparations contain higher concentrations of pathogen-specific antibodies than convalescent plasma. However, they are more difficult to produce and there are currently no SARS-CoV-2 hyperimmune globulin preparations available.
Neutralising monoclonal antibodies are a plausible therapeutic option against infectious diseases (Marston 2018). For example, a monoclonal antibody is licensed for prophylaxis against respiratory syncytial virus in at-risk infants. and mabs have been used to treat Ebola-patients (Marston 2018). Monoclonal antibodies against SARS-CoV have been tested in animal models and some were found to be effective. It is likely that mabs against SARS-CoV-2 will soon be developed and testet. As explained above (see section on antibody dependent disease enhancement) the possibility of antibody dependend disease enhancement needs to be ruled out before such mabs can be applied in humans.
Active immunization against SARS-CoV-2
At the time of this writing, there are more than 100 COVID-19 vaccine candidates in different stages of preclinical development. Five candidate vaccines are in phase I clinical trials (Thanh Le 2020).
The speed of 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. This was possible, thanks to knowledge gained in efforts to develop vaccines against SARS and MERS and the availability of innovative technologies.
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. A high degree of homology between the S proteins of the three viruses was quickly established after the discovery of SARS-CoV-2 and the interaction of SARS-CoV-2 S protein with ACE2 was confirmed. Thus, a vaccine target was identified in record time.
New technologies helped the rapid development of an mRNA-based vaccine. The principle was first used in 2013. The Chinese CDC had discovered H7N9, a novel avian influenza virus strain, and immediately published the sequence of the relevant antigens online. Synthetic biology approaches enabled the generation of a vaccine candidate within 8 days and that vaccine was shown to induce antibodies in mice (Hekele 2013).
Why, then, do we still wait for an effective and safe vaccine against SARS-CoV-2? There are still some obstacles to overcome.
Different strategies to develop a vaccine against SARS-CoV-2
Many fundamentally different strategies are currently used to develop a vaccine against COVID-19 (Amanat 2020).
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). Efforts are ongoing to develop attenuated or inactivated SARS-CoV-2 as a vaccine.
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.
A more recent approach is to use recombinant viral vectors in which a relevant antigen of the pathogenic virus is expressed. The only currently licensed example is the vaccine against Ebola, which is based on a modified vesicular stomatitis virus. An adenovirus-based recombinant vaccine against COVID-19 has entered a clinical phase I trial in March 2020.
DNA vaccines targeting the S protein are also in preclinical development. There are currently no licensed DNA vaccines, which might make the licensing process slower as compared with e.g. protein-based vaccines. A DNA vaccine against COVID-19 entered a clinical phase I trial in April 2020.
An mRNA vaccine targeting the S protein has been used in a clinical phase I trial that started on 16 March. There are currently no licensed mRNA vaccines, which might make the licensing process slower as compared with e.g. protein-based vaccines.
A vaccine based on genetically modified dendritic cells expressing a lentivirally encoded SARS-CoV-2 minigene and a study using genetically modified artificial antigen presenting cells entered a clinical phase I trial in March. There are currently no licensed vaccines based on genetically modified antigen-presenting cells, which might again make the licensing process slower as compared with e.g. protein-based vaccines.
While it is much too early to make any predictions on the safety, immunogenicity and efficacy of the many vaccines currently under development, it is useful to see what can be learned from prior attempts to develop vaccines against coronaviruses.
Vaccines against coronaviruses can induce pathological immune responses.
Rarely, vaccines can enhance disease rather than protect from disease (Openshaw 2001). Vaccines are administered to healthy people. SARS-CoV-2 causes a mild, if not clinically inapparent disease in at least 80% of those who are infected. Therefore, safety considerations are of utmost importance. Unfortunately, there is some data hinting at the possibility that the development of a safe vaccine against COVID-19 might be unusually difficult.
Vaccine-induced immune response against FIPV is harmful in kittens
Feline infectious peritonitis (FIP) is a severe and often fatal disease in cats. It is caused by a coronavirus, FIPV. Different attempts at vaccine development have failed. In an early study kittens that were vaccinated with an avirulent FIPV strain were more susceptible to infection with virulent FIPV than the non-vaccinated controls (Pedersen 1983). More worryingly were the results of a later study in which cats were immunized with a recombinant vaccinia virus that expressed the FIPV S protein. Vaccination induced low titers of neutralizing antibodies. Upon FIPV-challenge the previously immunized animals were not protected but died earlier than the controls (Vennema 1990). It is thought that antibody-mediated infection of macrophages and the deposition of immune complexes cause the more severe disease in immunized animals (Perlman 2005, Weiss 1981).
Immunopathology seen in experimental vaccines against SARS
Immunopathological or disease-enhancing effects were reported by many different research groups using different technologies and different animal models in an effort to develop a vaccine against SARS.
Immunization with recombinant modified vaccinia virus Ankara (rMVA) expressing the SARS-CoV spike (S) protein causes severe hepatitis in ferrets.
Ferrets are susceptible to SARS-CoV infection. Weingartl and collegues immunized ferrets with recombinant modified vaccinia virus Ankara (rMVA) expressing the SARS-CoV S protein (Weingartl 2004). Upon challenge with the virus, high titers of neutralizing antibodies were detectable more rapidly in the immunized animals than in the controls. However, the ferrets immunized with rMVA-S developed severe hepatitis which was not the case in the control animals (Weingartl 2004). Ferrets are also highly susceptible to SARS-CoV-2 infection (Kim 2020) and are thus suitable for the evaluation of the safety of future vaccine candidates.
Immunization of mice results in type 2 inflammatory responses in the lungs
A group from North Carolina, USA used inactivated virus with or without adjuvant to immunize mice against SARS-CoV (Bolles 2011). The vaccine protected young and to a lesser extent, older animals from morbidity and mortality following high-dose viral challenge. However, challenge with a heterologous virus resulted in inflammatory infiltrates and pulmonary eosinophilia that were more severe in the vaccinated animals. Moreover, in old mice the vaccine did not confer protection but still resulted in inflammatory infiltrates in the lung. The occurrence of lung immunopathology with this vaccine was later confirmed and extended by another group (Tseng 2012). Eosinophilic lung infiltrates were also observed when a recombinant baculovirus expressed S protein or coronavirus-like particles (VLPs) expressing the SARS-CoV S protein were used to immunize mice (Lokugamage 2008, Tseng 2012). It is important to note that these were mainly histopathological findings and the vaccinated mice had reduced viral titers upon challenge. However, these histopathological findings are reminiscent of those that were associated with vaccine-induced pathology in children that had received a vaccine against respiratory syncytial virus (RSV) in the 1960s (Castilow 2007). Moreover, lung pathology and even pneumonia were reported when mice were immunized with recombinant vaccinia virus (VV) expressing SARS-CoV S and nucleocapsid (N) proteins (Yasui 2008). Lung pathology was also observed when Venezuelan equine encephalitis virus replicon particles (VRP) expressing the N protein were used to immunize mice (Deming 2006).
Unfortunately, if perhaps not surprisingly, similar findings were reported for MERS-CoV vaccine candidates. An inactivated MERS-CoV vaccine induced neutralizing antibodies in mice and also resulted in an enhanced type 2 pathology in the lung, i.e. eosinophilic infiltrates and increased concentrations of IL-5 and IL-13 (Agrawal 2016).
Some studies suggest that this type 2 pathology may be ameliorated or prevented by using toll-like receptor agonists (Iwata-Yoshikawa 2014) or delta inulin (Honda-Okubo 2015) as adjuvants for inactivated whole virus or recombinant spike protein vaccine candidates.
Together, these findings cause concern. Careful histopathological evaluation of the lungs should be part of the pre-clinical development of COVID-19 vaccines.
Immunization of non-human primates results in severe acute lung injury
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). An earlier study had used inactivated SARS-CoV to vaccinate four macaques. Three monkeys were protected upon challenge whereas one macaque had lung-pathology consistent with antibody-dependent disease enhancement (ADE) (Wang 2016). These authors further suggested that ADE was mediated by antibodies against certain epitopes of SARS-CoV S but not others (Wang 2016).
Anti-S antibodies enhance infection of human immune cells
Antibodies against SARS-CoV spike protein can enhance virus entry into human cells by interaction with conformational epitopes in the ACE2-binding domain (Yang 2005). Anti-Spike immune serum was reported to promote the infection of human hematopoietic cell lines by SARS-CoV. Virus entry was not mediated via ACE2 but depended on Fcγ receptor II (Jaume 2011). While the in vivo relevance of these findings remains to be determined, they add to the list of concerns that need to be addressed in the development of safe and effective vaccines against COVID-19.
Given the massive and diverse ongoing efforts to develop a vaccine against COVID-19, we can be optimistic that a safe and effective vaccine will be available in the not-too-distant future. The development of a vaccine against Ebola took five years and there is reason to believe that the COVID-19 vaccine(s) will be developed even faster than that. We need to keep in mind that vaccine discovery and early development only require 30% of all the work and time required to bring a vaccine to the end user.
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.
A lesson that should have been learned already following the SARS outbreak is that more enzootic viruses will jump from their animal reservoirs to humans. Given the fact that not too many different viruses can cause severe and potentially deadly respiratory infections we should not stop our efforts once a SARS-CoV-2 specific vaccine is available. Instead, efforts should be made to develop a vaccine platform that can quickly be adapted to newly emerging coronaviruses. We do not know the date of the next outbreak, but we can be sure that SARS-CoV-2 is not the last coronavirus humankind will confront.
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