INTRODUCTION: One of the consequences of SARS-CoV-2 infections over the last year has been a large increase in reactivation of herpes viruses. There are numerous reports of COVID-19 patients with suspected reactivation of several different herpes viruses, including human herpesvirus 1 and 2 (HSV 1/2), varicella-zoster virus (VZV), human herpesvirus 6 and 7 (HHV 6/7), as well as cytomegalovirus (CMV). It is known that cell-mediated immunity plays an important role in herpes virus latency. COVID-19 infection decreases cell-mediated immunity by decreasing lymphocytes, such as CD3+, CD4+, and CD8+ T cells. These cells produce gamma interferon (IFN-γ) which is known to suppress reactivation of herpes viruses. So, if the IFN-γ levels are reduced, viral reactivation occurs. This report will discuss the reactivation of herpes viruses that leads to Bell’s palsy.

DISCUSSION: There are numerous (thousands) reports of COVID-19 patients who subsequently have been diagnosed with Bell’s palsy, such as the report by Neo et al1. Bell’s palsy is a common cause of lower motor neuron neuropathy and is known to occur upon the reactivation of either HSV 1/2 or from VZV. Serological studies have shown that the prevalence of antibodies to HSV among patients with Bell’s palsy is higher than that among healthy control subjects, which suggests that HSV may be involved in the pathogenesis of Bell’s palsy (Adour et al2).

In addition to HSV, VZV is known to play a role in Bell’s palsy. A portion of Bell’s palsy patients have what is called, Ramsay Hunt syndrome, but these patients have more severe paralysis at the onset and are less likely to recover completely (Sweeney and Gilden3). Patients with Ramsay Hunt syndrome are characterized by peripheral facial paralysis without ear or mouth rash, and the presence of either a fourfold rise in antibody to VZV or the detection of VZV DNA in skin, blood mononuclear cells, or middle ear fluid.

It is clear that the suppression of IFN-γ during a COVID-19 infection plays a role in reactivating herpes viruses. The ability of IFN-γ to control chronic herpes virus infection and reactivation from latency is known for many herpes viruses (Presti et al4). One interesting observation is that during the COVID-19 vaccination program, there have been 2,178 cases (through June 18, 2021) of Bell’s palsy associated with this vaccination campaign, as shown by the CDC vaccine adverse event reporting system (VAERS).

It is suspected that as the host immune system actively responds to the vaccine(s), the host immune system is initially suppressed, which could reduce host IFN-γ-producing T cells, thus leading to viral reactivation. Based on the VAERS case reports, the majority of these cases have been treated using antivirals that target herpes viruses, such as famciclovir, valacyclovir, and acyclovir, which is an indication of the known association between herpes virus reactivation and Bell’s palsy.

CONCLUSION: Over the last 18 months, there have been thousands of cases of Bell’s palsy associated with either being infected with SARS-CoV-2 or from being vaccinated against this virus. It would be prudent to test for herpes viruses (HSV 1/2 and VZV) if COVID-19-infected or recently vaccinated patients show Bell’s palsy symptoms.

REFERENCES:

  1. Neo W. L., Ng J.C.F., and Iyer N.G. (2020). The great pretender – Bell’s palsy secondary to SARS-CoV-2? Clinical Case Report, 9:1175-77. https://doi.org/10.1002/ccr3.3716
  2. Adour K.K., Bell D. N., and Hilsinger R.L.J. (1975). Herpes simplex virus in idiopathic facial paralysis (Bell palsy). JAMA 233:527-30. https://doi.org/10.1001/jama.1975.03260060037015
  3. Sweeney C.J., Gilden D. H. (2001). Ramsay Hunt syndrome. J Neurol Neurosurg Psychiatry 71:149-154. https://doi.org/10.1136/jnnp.71.2.149
  4. Presti R. M., Pollock J.L., Dal Canto A.J., O’Guin A.K., and Virgin H.W. (1998). Interferon gamma regulates acute and latent murine cytomegalovirus infection and chronic disease of the great vessels. J Exp Med. 188:577-88. https://doi.org/10.1084/jem.188.3.577

By David Kilpatrick, PhD and Abbas Vafai, PhD

MKTG 1061 – Rev A 070121

INTRODUCTION: Over the last six decades, there has been a steady increase in the number of herpes zoster (HZ, shingles) cases in the United States, including among younger adults.

A 2013 study (Hales et al1) found that rates of shingles have been climbing since the mid-1940s in all age groups. From 1945 to 1949, 0.76 out of every 1,000 people got the disease. Between 2000 and 2007, that number rose to 3.15 people per 1,000. The virus has hit older adults particularly hard. Shingles rates rose 39% from 1992 to 2010 in people over 65. It is now estimated that one in three (1 in 3) people will get HZ during their lifetime.

DISCUSSION: The rise in HZ cases is a complicated issue. Several factors are involved in these cases. As we discussed in a previous Viro Perspective, waning immunity in younger adults or the possible emergence of wild type alleles may be involved with cases seen in those under 50 years of age.

Immunosuppression is a key reason for HZ. Harpaz et al2 discussed the prevalence in immunosuppression in the U.S. They said that the number of immunosuppressed adults in the United States is unknown but thought to be increasing because of both greater life expectancy among immunosuppressed adults due to improvements in medical management, as well as new indications for immunosuppressive treatments.

Immunosuppression increases the risks and severity of primary or reactivation infections. There are many examples of this, such as in the case of a 67-year-old woman with non-Hodgkin’s lymphoma who was undergoing chemotherapy and who presented with an acute alteration of consciousness due to multiple brain lesions3. MRI of the brain revealed multiple and nonspecific lesions of hyperintensity with mild edema in the cortex and subcortex. She was treated with intravenous acyclovir. However, two days after admission, the patient died and was diagnosed with varicella-zoster virus (VZV) encephalitis. This case highlights the risk of VZV reactivation with severe neurological complications in patients undergoing immunosuppressive therapy.

In another example, there was HZ of the trigeminal nerve with multi-dermatomal involvement4. This was an unusual example of HZ with involvement of both the ophthalmic and maxillary divisions of the trigeminal nerve in an immunocompetent patient. Immunocompetence status and age-specific screening should be warranted in case of atypical involvement and according to the patient’s history, while treatment with antiviral drugs should be rapidly initiated in patients at risk. The 2020 pandemic with SARS-CoV-2 is also showing a correlation of COVID-19 infection with the reactivation of VZV, leading to HZ.

CONCLUSION: There is no single cause for the rise in the reactivation of VZV, however it is apparent that the increase in immunosuppression is key. The use of immunosuppressive drugs to prevent other diseases is common, such as in battling cancer. Many other infections also lower the immunocompetence of an individual. It is known that an active immune response producing interferons helps to keep VZV reactivation in check. It is also known that SARS-CoV-2 infections reduce lymphocytes, monocytes, and eosinophils, along with noted reductions of CD4/CD8 T cells, B cells, and natural killer cells. This results in lymphopenia due to the direct infection of lymphocytes with SARS-CoV-2, activation-induced cell death, and impairment to antiviral responses (such as with specific interferons). At some point, it should be investigated if these HZ cases can be reduced using the SHINGRIX vaccine in those under 50.

REFERENCES:

  • Pelloni, L.S., Pelloni, R., and Borradori, L. (2020). Herpes zoster of the trigeminal nerve with multi-dermatomal involvement: a case report of an unusual presentation. BMC Dermatology 20:12 https://doi.org/10.1186/s12895-020-00110-1

By David Kilpatrick, PhD and Abbas Vafai, PhD

MKTG 1060 – Rev A 060321

INTRODUCTION: Varicella-zoster virus (VZV) causes chickenpox, an acute viral, vesicular, exanthematous illness. After primary infection, VZV often becomes latent in ganglionic neurons, without production of viral proteins or infectious particles. In recent years, there have been numerous reports of children vaccinated with the live attenuated vaccine virus strain VZV vOka coming down with herpes zoster (HZ)1,2.

DISCUSSION: The effectiveness of the varicella vaccination program has been very good, with the occurrence of chickenpox virtually disappearing. However, more cases of viral reactivation leading to HZ have been seen in recent years among children vaccinated with vOka. The most serious complication in healthy children is the central nervous system infection. This is caused by reactivation of the vaccine virus from the dorsal root ganglia (DRG), usually years after the first varicella vaccination. Heusel and Grose1 looked at 12 cases of varicella vaccine meningitis.

The vOka vaccine strain was given to children in the United States for 26 years. It was approved in 1995 by the U.S. Food and Drug Administration as a single-dose regimen around age one year. Since 2012, Heusel and Grose have located eight cases of varicella vaccine meningitis in once-immunized children. Two of the eight children who received a single vaccine dose and developed varicella vaccine meningitis were immune-compromised. The other six children had no known immunosuppression. All of the children had HZ preceding onset of meningitis. However, there was an unusual aspect about the dermatomal distribution – usually a band of rash/blisters going around the waist.

Six of the eight zoster rashes were in a cervical dermatome (rash around the neck-shoulder-arm). Typical distribution of HZ following wild-type varicella include dermatomes T3-T10 and cranial nerve V (trigeminal ganglion). When the varicella vaccine was first approved in the U.S., there was a long catch-up period when older children could be immunized. It is most likely that several children in the study were immunized in the arm, rather than the thigh because they were older. Thus, they developed HZ in the cervical dermatomes. The current recommendation is for all children to have their first vaccine dose in the thigh around age one year.

A Medline literature search between 1960 and 2004 found only one case of HZ meningitis. Since 2017, four such cases in twice-immunized adolescents have been reported. In 2006, the FDA recommended a change from one to two doses with the first dose at age one and the second before entry to primary school (4-6 years). The belief was that varicella vaccine meningitis would not occur in children who had received two vaccine doses. This assumption has now proven to be incorrect. In contrast to children who had received only a single immunization, the time interval between first vaccination and the onset of varicella vaccine meningitis was constant; all four children were 14 years old.

The general pathogenesis is that following varicella vaccination in 50% of the children, the virus is carried within lymphocytes throughout the body. Some virus enters and becomes latent in the trigeminal ganglion, and when the virus reactivates, it can be carried via afferent fibers to the meninges, cerebral arteries, and eyes (herpes zoster ophthalmicus or HZO). Of the 12 published cases of HZ meningitis caused by the vaccine virus, only one case of HZO was seen.

CONCLUSION: The authors offered no consensus in explaining the varicella vaccine cases in immunized, immunocompetent children. They proposed several possible explanations:

(i) Waning immunity, as some military personnel who had received vaccination were 24% less likely to be VZV-seropositive than those recruits who had wild-type varicella as children;

(ii) Differential immune responses to vaccination vs. the varicella disease, perhaps due to quantitative differences in duration of their respective antibody responses (vaccine virus vs. wild-type virus). Here, a lowered antibody response to the major VZV structural glycoprotein (gC) was seen in immunized children vs. the VZV gC, which is a major component of wild-type VZV virions found abundantly in skin vesicles. During infection after vaccination, there is little or no formation of vesicles in the skin, thus much less VZV gC is produced; and

(iii) Emergence of wild-type alleles in the viral genome during reactivation of varicella vaccine virus as HZ.

The authors noted that in a case reported in 2019 of a severe HZ from the varicella vaccine virus, they observed the open reading frame (ORF) 0 had reverted to a wild-type allele2. Therefore, HZ was more severe in that child.

 

REFERENCES:

  1. Ethan H. Heusel and Charles Grose. (2020). Twelve Children with Varicella Vaccine Meningitis: Neuropathogenesis of Reactivated Live Attenuated Varicella Vaccine Virus. Viruses 2020, 12, 1078;1-13. https://doi.org/10.3390/v12101078
  2. Moodley, A., Swanson, J., Grose, C., and Bonthius, D.J. (2019). Severe Herpes Zoster Following Varicella Vaccination in Immunocompetent Young Children. Child Neurol. 34, 184-188. https://doi.org/10.1177/0883073818821498

By David Kilpatrick, PhD and Abbas Vafai, PhD

MKTG 1057 – Rev A 041821

INTRODUCTION: This is an update from our earlier report (Part II) regarding the use of the SARS-CoV-2 spike protein with two different adjuvants. The Phase I clinical trial results were presented in The Lancet by Richmond et al1. This was the first human trial of this subunit vaccine and was used to find the proper antigen dose and adjuvant justification using the stabilized trimeric spike subunit protein vaccine (SCB-2019). They used a Trimer-Tag method – a protein derived from the C-terminus of human type 1 procollagen that preserves the trimeric conformation of the SARS-CoV-2 spike protein, which has not been previously used in clinical trials.

DISCUSSION: This Phase I trial was a randomized, double-blind placebo-controlled trial in Australia. They enrolled two age groups, ages 18-54 and ages 55-75. Participants were randomly allocated to either the placebo or vaccine group. They received 2 doses of a placebo (0.9% NaCl) or SCB-2019 (either 3 µg, 9 µg or 30 µg) at 21 days apart. The vaccine either had no adjuvant (only the S-trimer protein)or was adjuvanted with AS03 (GSK Corporation) or CpG/Alum (Dynavax Technologies). Immune response was assessed for seven days after each vaccination. Humoral responses were measured as SCB-2019 binding IgG antibodies and ACE2-competitive blocking IgG antibodies by ELISA and as neutralizing antibodies by wild-type SARS-CoV-2 microneutralization assay. Cellular responses to pooled S-protein peptides were measured by flow-cytometric intracellular cytokine staining. 148 participants were followed for up to 4 weeks after 2nd dose. Vaccination was well tolerated with two grade-3 solicited adverse events (pain in 9 µg ASO3-adjuvanted and 9 µg CpG Alum-adjuvanted groups). Most local adverse events were mild injection-site pain, and local events were more frequent with formulations containing AS03 adjuvant (44-69%) than with those containing CpG/Alum adjuvant (6-44%) or no adjuvant (3-13%). Systemic adverse events were more frequent in younger adults (38%) than in older adults (17%) after the first dose but increased to similar levels in both age groups after the second dose (30% in older and 34% in younger adults). No consistent trends or clinically significant laboratory safety abnormalities were noted in any group at any timepoint. No cases of SARS-CoV-2 infection were reported during the study. No adverse events of special interest, including potential immune-mediated diseases were seen. This is of great interest due to past reports of vaccine-associated disease enhancement (VADE) seen with previous Coronavirus vaccines, such as for the development of vaccines for SARS in 20032. Anti-SCB2019 IgG antibodies did not increase after the first dose of non-adjuvanted SCB-2019 by day 22, irrespective of dose level. By day 50, three SCB-2019 recipients seroconverted, one of eight in the 3µg group and two of seven in the 30µg group. In both adjuvanted cohorts, SCB-2019 dose-dependent IgG responses were evident after a single dose in both age groups. All participants at each dose level of SCB-2019 with AS03 adjuvant seroconverted by day 36. After the 2nd dose of SCB-2019 with AS03 adjuvant, a very large increase in antibody geometric mean titers (GMTs) was seen; levels higher than those seen with convalescent serum samples and NIBSC reference serum. Antibody titers persisted at high levels at day 50. Small dose-dependent IgG responses against SCB-2019 with CpG/Alum adjuvant were seen at all dose levels at day 22 after one dose in young adults, which greatly increased after the 2nd dose. High GMTs were maintained to day 50. The vaccine with fixed doses of either AS03 or CpG/Alum adjuvants induced high titers and seroconversion rates of binding and neutralizing antibodies in both younger and older adults (anti-SCB2019 IgG antibody GMTs at day 36 were 1567-4452 with AS03 and 174-2440 with CpG/Alum).

CONCLUSION: This report shows high level neutralizing antibody responses, with a Th1-biased cellular immune response and an acceptable safety profile. Based on these results, 9 µg SCB-2019 adjuvanted with AS03 and 30 µg SCB-2019 adjuvanted with CpG/Alum were the preferred candidates to be used in the phase 2/3 trial.

REFERENCES:
1. P. Richmond, L. Hatchuel, M. Dong, B. Ma, B. Hu, I. Smolenov, P. Li, P. Liang, H.H. Han, J. Lian, and R. Clemens. 2021. Safety and immunogenicity of S-Trimer (SCB-2019), a protein subunit vaccine candidate for COVID-19 in healthy adults: a phase 1, randomized, double-blind, placebo-controlled trial. The Lancet, Jan 29 2021, https://doi.org/10.1016/S0140-6736(21)00241-5
2. S. Su, L. Du, and S. Jiang. 2021. Learning from the past: development of safe and effective COVID-19 vaccines. Nature Reviews 19,211-219. https://doi.org/10.1038/s41579-020-00462-y

INTRODUCTION: Shingles, or herpes zoster (HZ), is an acute, viral infection that occurs after the reactivation of the varicella-zoster virus (VZV). The virus usually remains dormant within dorsal root ganglia after the virus’s primary infection presentation in the form of varicella. HZ is thought to appear when the immune system is under stress due to a recent illness, emotional stress, immunosuppression, or even exposure to excessive sunlight (UV rays). HZ has been observed in numerous patients during the COVID-19 viral outbreak over the last year. Data is being accumulated that points to COVID-19 infections triggering the occurrence of HZ.

DISCUSSION: As reported by Elsaie et al1, it has been confirmed by many that a COVID-19 infection is accompanied by a reduction in lymphocytes, monocytes, and eosinophils, along with noted reductions of CD4/CD8 T cells, B cells, and natural killer cells. Different mechanisms for lymphocyte depletion and deficiency have been speculated among COVID-19 patients. It has been postulated that the functional damage of CD4+ T cells may predispose patients with COVID-19 to severe disease. Such immune changes can render a patient more susceptible to developing shingles by reactivating VZV, which could be a sign of undiagnosed COVID-19 infection in younger age groups, according to the authors in this report.

Two earlier reports discussed HZ among COVID-19 diagnosed patients. Shors et al2, presented a case of a patient who developed HZ during a course of COVID-19 infection. This patient also developed severe acute herpetic neuralgia despite the early initiation of antiviral therapy. Elsaie et al3, described two cases of patients who presented with HZ before later being diagnosed with COVID-19 infection. In the earlier report, Elsaie et al1 reported a pregnant female who presented with HZ during the course of a COVID-19 infection. They speculated that HZ may be a marker for COVID-19 infection, especially in younger patients.

In another report, Saati et al4 presented a case of an immunocompetent middle-aged male who had COVID-19 in combination with HZ. They postulated that there may be an association between COVID-19 and reactivation of VZV in the form of HZ. In patients who present with HZ in the current pandemic of COVID-19, they believe it would be prudent to adhere to taking precautions until the diagnosis of COVID-19 is excluded.

CONCLUSION: There are many reports, in addition to those presented here, which show a correlation between COVID-19 infection and reactivation of VZV, leading to HZ. A possible explanation of HZ in COVID-19 patients may be related to the decrease in total lymphocyte count in these patients. Lymphopenia occurs as a result of the direct infection of lymphocytes with SARS-CoV-2, activation-induced cell death, and impairment to antiviral responses. As various cutaneous manifestations of COVID-19 disease are increasingly being reported, clinicians should be on the alert for HZ, which may be a complication or an indicator of COVID-19 infection, particularly in younger patients.

REFERENCES:
1. Elsaie, M.L., Eman A. Youssef, and Hesham A. Nada. 2020. Herpes Zoster May Be a Marker for COVID-19 Infection During Pregnancy. Cutis, 106:318-320. https://doi.org/10.12788/cutis.0133
2. Shors, A.R. 2020. Herpes zoster and severe acute herpetic neuralgia as a complication of COVID-19 infection. JAAD Case Rep. 2020;6:656-657. https://doi:10.1016/j.jdcr.2020.05.012
3. Elsaie, M.L., Eman A. Youssef, and Hesham A. Nada. 2020. Herpes zoster might be an indicator for latent COVID-19 infection. Derma Therapy 33 e13666. https://doi.org/10.1111/dth.13666
4. Saati, A., Faisal Al-Husayni, Afnan A. Malibari, Anas A. Bogari, and Maher Alharbi. 2020. Herpes Zoster Co-Infection in an Immunocompetent Patient with COVID-19. Cureus 12(7): e8998.

INTRODUCTION: In the last several years, a new approach to viral vaccine design has shown great promise. Vaccine makers are looking to see if the success can be replicated with other vaccines. Shingles is a viral infection that is caused by reactivation of varicella zoster virus (VZV), causing chickenpox upon primary exposure. The incidence of shingles increases with age due to the decline in natural immunity. In some populations, such as those in Australia, data shows that approximately 50% of the population will develop shingles. Vaccination is the only way to reduce the number of shingles cases. Research has shown that the SHINGRIX vaccine produces a 24-fold increase in T cells, which is 12 times higher than other less effective shingles vaccines. The possible explanation for this boost in long term immunity to shingles was presented in a paper by Cunningham et al1.

DISCUSSION: In October 2017, the FDA approved SHINGRIX (Zoster Vaccine Recombinant, Adjuvanted) for the prevention of herpes zoster (shingles) in adults aged 50 years and older. The previous live attenuated VZV vaccine (Zostavax, Merck Sharpe & Dohme Corp.) showed reduced efficacy as age increases, declining to only 18% in those over 80 years of age. The recombinant glycoprotein E (gE) subunit vaccine, SHINGRIX was developed to overcome these efficacy limitations due to age. This vaccine contains the recombinant VZV gE protein and the AS01B adjuvant system. It is suspected that the use of a single viral glycoprotein with this adjuvant is responsible for the 24-fold increase in CD4 T-cell responses to this vaccine. Cunningham et al1 discusses the details of this adjuvant system. AS01B contains Quillaja sponaria Molina, fraction 21 (QS21; licensed by GSK from Antigenics LLC- Agenus Inc) and 3-O-desacyl-4′-monophosphoryl lipid A (MPL). AS01B stimulates a local and transient activation of the innate response leading to the recruitment and activation of antigen-presenting dendritic cells. QS21 is an adjuvant that induces transient local cytokine responses and activation of dendritic cells and macrophages in muscle and draining lymph nodes in animal models. The toll-like receptor type 3 agonist MPL synergizes with QS-21 to enhance the immune response to the co-administered antigen through the production of interferon-gamma (IFN-γ). Phase I and II trials demonstrated that a single vaccine dose elicits substantial humoral and cell mediated immune (CMI) responses that further increase after a second dose two months after the initial dose. Each vaccine dose combines 50 µg purified gE with the AS01B adjuvant containing MPL (50 µg), QS-21 (50 µg) within liposomes. Overall, vaccine recipients ≥50 years of age showed a 24.6-fold increase in gE-specific CD4 cells. This is in comparison to placebo recipients (saline only) where there was no change in gE-specific CD4 T-cell frequencies after vaccination at any time point. Humoral responses were elevated in all age groups throughout the 36-month observation, with slightly lower immune response in those over age 70 years. While a high, persistent circulating antibody response is induced, gE-specific CMI is believed to be the main mechanistic driver of protection against herpes zoster. The phase II clinical trials induced a gE-specific CMI response in > 90% of recipients. Peak CD4 T-cell frequencies were observed at 1 month following dose 2, then declined substantially by 12 months after dose 2, and remained stable for the remainder of the study. This vaccine has a multi-fold increase in humoral and CMI responses compared to the previous live-attenuated vaccine. It is thought that the ability of SHINGRIX to elicit this substantial immune response in older age groups is likely due to the capacity of AS01B Adjuvant System to enhance gE-antigen presentation by increasing the number of activated antigen-presenting cells. In addition, AS01 promotes T-cell responses through a synergistic effect between MPL and QS-21, involving the stimulation of macrophages in the draining lymph node and early IFN-γ production, which in turn mediates the effects on dendritic cells. Cunningham suggests another factor possibly enhancing the immune response is that the previous live-attenuated vaccine induces a broad response against multiple antigens, while the SHINGRIX vaccine immune response is directed against a single immunodominant antigen, which indicates that a strong narrowly focused immune response can be highly protective, even against a complex viral pathogen that possesses multiple immune evasion pathways.

DISCUSSION: Two doses of the SHINGRIX vaccine induced robust humoral and cellular immune responses in all age groups (especially people ≥70 years). It is thought that the ability of this vaccine to induce such persistent antibody and polyfunctional CD4 T-cell responses in older adults is due to using a single viral antigen in combination with the use of the AS01B adjuvant system which apparently can overcome the immunosenescence seen with age.

  1. REFERENCES:
    1) Anthony L. Cunningham, T.C. Heineman, H. Lal, O. Godeaux, R. Chlibek, S.-J. Hwang, J. E. McElhaney, T. Vesikari, C. Andrews, W. S. Choi, M. Esen, H. Ikematsu, M. K. Choma, K. Pauksens, S. Ravault, B. Saluan, T. T. Schwarz, J. Smetana, C. V. Abeele, P. Van-den-Steen, I. Vastiau, L. Y. Weckx, and M. Levin. (2018). Immune Responses to a Recombinant Glycoprotein E Herpes Zoster Vaccine in Adults Aged 50 Years or Older. JID 2018:217;1750-1760. https://DOI.org/10.1093/infdis/jiy095

INTRODUCTION: In this follow-up report, we discuss several adjuvanted SARS-CoV-2 subunit vaccines in development. In general, subunit vaccines exhibit low immunogenicity and require assistance from an adjuvant to enhance a robust vaccine-induced immune response. The S glycoprotein of SARS-CoV-2 is the preferred viral protein to induce neutralizing antibodies due to its known immunogenic properties. The S glycoprotein possesses two conformational states—a pre-fusion and a post-fusion state. The vaccine antigen must preserve the epitopes in these two conformational states to elicit a good antibody response. There are several SARS-CoV-2 vaccine trials in various clinical Phases, which are using either the GSK adjuvant AS03 (Sanofi & GSK), CpG 1018 from Dynavax (Novavax), or using both adjuvants (Clover Biopharmaceuticals trial).

DISCUSSION:  Liang et al.1 presented results from using both adjuvants. The trimeric spike protein (S) of SARS-CoV-2 binds to ACE2 (angiotensin-converting enzyme)—the host cell surface receptor—and mediates the viral entry via membrane fusion. Based on the recent history of developing vaccines against coronaviruses (such as SARS in 2003 and MERS in 2012), there are at least two challenges in producing safe and effective vaccines against these RNA viruses. The first challenge is inducing broad neutralizing antibodies. The second challenge is reducing or eliminating the possibility of vaccine-associated enhanced respiratory disease, as seen in the case of Respiratory Syncytial Virus (RSV) and SARS vaccines. Liang et al.1 described using a Trimer-Tag platform with a tailored subunit antigen (S glycoprotein) derived from the wild-type viral sequences. The S glycoprotein was subcloned into the pTRIMER mammalian expression vector to allow in-frame fusion to Trimer-Tag, capable of self-trimerization via disulfide bonds. The column purified the S-Trimer protein, which was secreted by CHO cells in a serum-free culture medium. The column bound S-Trimer was purified to near homogeneity in a single step.

Mice immunized with the S-Trimer and an adjuvant of either ASO3 or CpG 1018 induced high levels of neutralizing antibodies. They further studied the immunogenicity of the adjuvanted S-Trimer in nonhuman primates (rhesus macaques). High levels of binding and neutralizing antibody titers were seen, including a boost-effect after the 2nd dose on Day 21. Upon challenge (Day 35) with the SARS-CoV-2 virus, animals were protected from body weight loss and body temperature increases. Complete reduction of viral loads was seen in necropsy lung tissue in both ASO3 and CpG 1018 (plus alum) adjuvanted S-Trimer groups. In contrast, viral loads were detectable in the non-vaccinated (viral challenged) group. This study showed significant adjuvant effects occur with both AS03 and CpG 1018 plus alum with the robust high-level induction of humoral and cell-mediated immune responses to S-Trimer in rodents and nonhuman primates.

Interestingly, Liang et al.1 noted some differences in the immune responses stimulated by these two adjuvant systems. In nonhuman primates, AS03 appeared to induce a stronger humoral immune response, inducing higher levels of neutralizing antibody titers than CpG 1018 plus alum. However, there were no apparent differences in the immune protection against the SARS-CoV-2 challenge observed between the two adjuvant systems in nonhuman primates. The critically important finding was no observation regarding disease enhancement signs, a theoretical concern based on prior experience with vaccine candidates against SARS-CoV-2 and RSV that utilized inactivated viruses.

CONCLUSION: Clinical trials with the SARS-CoV-2 S protein adjuvanted with either AS03 or CpG 1018 plus alum can induce robust humoral and cellular immune responses in various animal species giving protective immunity against SARS-CoV-2 infection in nonhuman primates, with no signs of disease enhancement. This last point is significant since current vaccines using either mRNA, DNA-vector, or inactivated virus vaccines have either done limited animal trials—or bypassed them altogether—to rush them into the market. As these subunit vaccines work their way through clinical trials—Novavax just entered a Phase 3 trial with CpG 1018 adjuvanted S-protein in late December 2020—we will provide updates.

  1. REFERENCES:
    1. Liang, J. G., Su, D., Song, T.-Z., Zeng, Y., Huang, W., Wu, J., Xu, R., Luo, P., Yang, X., Zhang, X., Luo, S., Liang, Y., Li, X., Huang, J., Wang, Q., Huang, X., Xu, Q., Luo, M., Huang, A., Luo, D., Zhao, C., Yang, F., Han, J.-B., Zheng, Y.-T., & Liang, P. (2020). S-Trimer, a COVID-19 subunit vaccine candidate, induces protective immunity in nonhuman primates. bioRxiv. https://doi.org/10.1101/2020.09.24.311027

MKTG 1053 Rev A – 010821

INTRODUCTION: Over the last several decades, subunit vaccines have shown consideration for vaccines. About 30 years ago, scientists developed a potential subunit vaccine for the varicella-zoster virus (VZV).1 A subunit vaccine’s advantage is several-fold, including not needing to grow and inactivate live viruses (or create an attenuated virus strain) and use the most antigenic portion of the virus antigen in question.

 

DISCUSSION: The key to this vaccine is that, unlike the live attenuated VZV vaccine, latency cannot be established when only a part of the virus protein (antigen) is used as the vaccine. In the subunit VZV vaccine’s initial stages, the VZV glycoprotein E (gE ) expresses in a recombinant vaccinia virus vector. Since regulatory agencies did not approve recombinant vaccinia vectors, scientists needed a different path. They constructed secretory truncated VZV glycoprotein gE with 511 amino acids into a vaccinia virus vector which would secret the glycoprotein. Next, they purified this from tissue culture fluids of the infected cells. The secreted gE protein-induced complement-dependent neutralizing antibodies in rabbits. Subsequent research showed that a VZV seropositive individual, when immunized with purified VZV gE in combination with an adjuvant, produced neutralizing antibodies.2  In the subsequent 20 years, GlaxoSmithKline’s clinical phase trials showed promising results with the truncated gE protein. As a result, the US Food and Drug Administration approved the VZV subunit vaccine (which used a GSK proprietary Adjuvant System, ASO1B), now called SHINGRIX, on Oct 20, 2017. Tavares-Da- Silva et al.3 found that based on the sale data from February 2019, with 9.4 million doses of vaccine, the efficacy (>90%) and the vaccine’s safety continue to mirror the clinical trials’ results. With the success of SHINGRIX, others have been encouraged to develop viral subunit vaccines. For example, respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infection in infants. Ensuing, scientists developed a recombinant RSV fusion glycoprotein (RSV F subunit). Leroux-Roels et al.4 found a single dose of the RSV subunit F vaccine was well-tolerated and enhanced pre-existing neutralizing antibodies through six months of follow-up. Awasthi, Hook, Shaw, and Friedman5 explain the development of a trivalent herpes simplex virus type 2 (HSV-2) vaccine using HSV-2 glycoproteins C, D, and E (gC2, gD2, gE2) using an alum adjuvant. This trivalent vaccine reduced the frequency of recurrent genital lesions and vaginal shedding of HSV-2 DNA by 50% (shedding of the replication-competent virus was almost eliminated). This result suggests the trivalent vaccine is a worthy candidate for immunotherapy of genital herpes. Furthermore, Tai et al.6 found that using a subunit vaccine containing the envelope protein of Zika is a strong candidate with high efficiency in preventing Zika virus infections in mice.

CONCLUSION: Subunit vaccines are being designed for many virus infections, based, in part, on the successful design and use of the VZV subunit vaccine, SHINGRIX. Only including the most immunogenic components of the virus antigenic protein in a vaccine offers many advantages, not the least of which is not needing to grow a live virus (whether an attenuated strain or a live virus to be inactivated before vaccination). Additional subunit vaccines will be appearing in the not-too-distant future.

 

REFERENCES:

  1. Vafai, A. (1993). Antigenicity of a candidate varicella-zoster virus glycoprotein subunit vaccine. Vaccine, 11(9) 937-940. https://doi.org/10.1016/0264-410x(93)90382-8
  2. Vafai, A. (1995). Boosting immune response with a candidate varicella-zoster virus glycoprotein subunit vaccine. Vaccine, 13(14), 1336-1338. https://doi.org/10.1016/0264-410x(94)00073-v
  3. Tavares-Da-Silva, F., Co, M. M., Dessart, C., Hervé, C., López-Fauqued, M., Mahaux, O.,  Van Holle, L., & Stemann, J.-U. (2019). Review of the initial post-marketing safety surveillance of the recombinant zoster vaccine. Vaccine, 38(18), 3489-3500. https://doi.org/10.1016/j.vaccine.2019.11.058
  4. Leroux-Roels, G., De Boever, F., Maes, C., Nguyen, T. L.-A., Baker, S., & Gonzalez, A. (2019). Safety and immunogenicity of a respiratory syncytial virus fusion glycoprotein F subunit vaccine in healthy adults: Results of a phase 1, randomized, observer-blind, controlled, dosage-escalation study. Vaccine, 37(20), 2694-2703. https://doi.org/10.1016/j.vaccine.2019.04.011
  5. Awasthi, S., Hook, L. M., Shaw, C. E., & Friedman, H. M. (2017). A trivalent subunit antigen glycoprotein vaccine as immunotherapy for genital herpes in the guinea pig genital infection model. Human Vaccines & Immunotherapeutics, 13(12), 2785-2793. https://doi.org/10.1080/21645515.2017.1323604
  6. Tai, W, Chen, J., Zhao, G., Geng, Q., He, L., Chen, Y., Zhou, Y., Li, F., and Du, L. (2019). Rational design of Zika virus subunit vaccine with enhanced. Journal of Virology, 93(17), e02187-18. https://doi.org/10.1128/JVI.02187-18

MKTG 1052 Rev A – 112420

INTRODUCTION

Herpes zoster (HZ) is caused by reactivation of latent varicella-zoster virus (VZV) within the cranial nerve or dorsal root ganglia after primary infection. There is a lifetime risk, ~10% to 30%, of HZ in adults, but is rare in healthy children. Immunocompromised individuals have an increased risk of other diseases, including HZ. Risk of HZ increases by age and a weakened immune system, especially in poor T-cell immunity. In children with cancer, HZ can lead to severe complications, including severe postherpetic neuralgia, visceral dissemination, acute or progressive outer retinal necrosis, and even death. Limited information is available on HZ in children with cancer. Lin et al.1 performed a nationwide population-based cohort study in Taiwan to estimate the incidence of HZ in children with cancer. The study, conducted on the sizeable data-scale dataset available from the National Health Insurance (NHI) program in Taiwan, explored HZ and cancer’s association.

DISCUSSION

In a study by Lin et al.1 , they identified 4,432 newly diagnosed children with cancer between 2000 and 2007 from the outpatient database. As a non-cancer control group, 17,653 children without cancer were frequency matched by sex and age. The average ages at the entry of the cancer group and non-cancer groups were 8.90 and 8.91 years, respectively. The distributions of age at entry, sex, urbanization level, or residential areas, and the prevalence of atopic dermatitis were similar in the two groups. All children received follow-up until death, HZ event, withdrawal from NHI, or end of December 2008. Children with cancer had a significantly lower prevalence of allergic rhinitis and bronchial asthma. The study demonstrated a higher incidence of HZ in children with cancer. The incidence rate of HZ in the population of 4,432 children with cancer was 20.7 per 10,000 person-years, and the incidence rate in the population of 17,653 without cancer was 2.4 per 10,000 person-years. The cumulative incidence was significantly higher in the cancer group (p < 0.0001, or 8.6 times higher). HZ may occur more frequently in children with cancer. More than 80% of children with lymphoma or acute leukemia developed HZ within two years of a cancer diagnosis. A study by Feldman, Hughes, and Kim 2 reported that the overall incidence of HZ in 1,132 children with cancer was 8.9%, and the incidence was 22% higher in patients with Hodgkin disease. Menon and Wan Maziah 3 identified a diagnosis of HZ in 5% (10/188) of the children with cancer and noted the most common malignancy in their study was leukemia.

CONCLUSION

Lin et al.1  found the incidence rates of HZ was 8.6-fold higher in children with cancer than those without cancer. They found that children with cancer were associated with an increased risk of HZ, with those who had leukemia having the highest magnitude of strength association. Early antiviral therapy is mandatory for immunocompromised patients. They concluded that vaccination with either heat-treated zoster vaccine or adjuvanted subunit vaccine (SHINGRIX) could be an appropriate policy to decrease herpes zoster incidence in children with cancer.

REFERENCES

  1. Lin, H.-C., Chao, Y.-H., Wu, K.-H., Yen, T.-Y., Hsu, Y.-L., Hsieh, T.-H., Wei, H.-M., Wu, J.-L., Muo, C.-H., Hwang, K.-P., Peng, C.-T., Lin, C.-C., & Li, T.-C. (2016). Increased risk of herpes zoster in children with cancer: A nationwide population-based cohort study. Medicine, 95(30), e4037. https://doi.org/10.1097/md.0000000000004037
  2. Feldman, S., Hughes, W. T., & Kim, H. Y. (1973). Herpes zoster in children with cancer. American Journal of Diseases of Children, 126(2), 178-184. https://doi.org/10.1001/archpedi.1973.02110190156009
  3. Menon, B. S., Wan Maziah, W. M. (2001). Herpes zoster in children with cancer. The Malaysian Journal of Pathology, 23(1), 47-48. Retrieved from https://europepmc.org/article/med/16329548

By David Kilpatrick, PhD and Abbas Vafai, PhD

MKTG 1051 Rev A – 110220

INTRODUCTION:
In the first nine months of 2020, it is becoming increasingly clear that being infected with the severe acute respiratory syndrome Coronavirus 2 (SARSCoV-2), now commonly referred to as COVID-19, may lead to the reactivation of varicella-zoster virus (VZV), causing herpes zoster (HZ). Read more