Possible Cross-Reactivity between SARS-CoV-2 Proteins, CRM197 and Proteins in Pneumococcal Vaccines May Protect Against Symptomatic SARS-CoV-2 Disease and Death

Abstract

Various studies indicate that vaccination, especially with pneumococcal vaccines, protects against symptomatic cases of SARS-CoV-2 infection and death. This paper explores the possibility that pneumococcal vaccines in particular, but perhaps other vaccines as well, contain antigens that might be cross-reactive with SARS-CoV-2 antigens. Comparison of the glycosylation structures of SARS-CoV-2 with the polysaccharide structures of pneumococcal vaccines yielded no obvious similarities. However, while pneumococcal vaccines are primarily composed of capsular polysaccharides, some are conjugated to cross-reacting material CRM197, a modified diphtheria toxin, and all contain about three percent protein contaminants, including the pneumococcal surface proteins PsaA, PspA and probably PspC. All of these proteins have very high degrees of similarity, using very stringent criteria, with several SARS-CoV-2 proteins including the spike protein, membrane protein and replicase 1a. CRM197 is also present in Haemophilus influenzae type b (Hib) and meningitis vaccines. Equivalent similarities were found at lower rates, or were completely absent, among the proteins in diphtheria, tetanus, pertussis, measles, mumps, rubella, and poliovirus vaccines. Notably, PspA and PspC are highly antigenic and new pneumococcal vaccines based on them are currently in human clinical trials so that their effectiveness against SARS-CoV-2 disease is easily testable.

Keywords: BCG; COVID-19; CRM197; PsaA; PspA; PspC; SARS-CoV-2; Streptococcus pneumoniae; cross-reactivity; diphtheria–tetanus–pertussis; measles–mumps–rubella; meningococcus; pneumococcal; poliovirus; protection; similarity; vaccination; vaccine.

Figure 1

Similarities between the four known or probable pneumococcal vaccine protein contaminants PsaA, PspA, PspC, Gram-positive anchor protein and SARS-CoV-2 proteins, as well as CRM197, the modified diphtheria toxin to which pneumococcal conjugate vaccines are attached. Multiple variants for each protein were examined and the results provided here are representative of results at E = 0.1.

Figure 2

Similarities between nine SARS-CoV-2 proteins and 32 proteins from measles, mumps, rubella, polio, Haemophilus influenzae type B (Hib), meningitis, diphtheria, pertussis and tetanus vaccines (Table 1). A total of 288 pairwise combinations were searched. Only similarities satisfying the criteria laid out in the Methods section are shown with E = 0.1.

Figure 3

SARS-CoV-2 protein similarities with Mycobacterium tuberculosis (Mtb). Note that BCG, unlike the vaccines in Figure 1 and Figure 2 that are composed of one to seventeen proteins, is composed of 3993 proteins, so that even given the somewhat larger number of significant similarities displayed here, the probability of them being major antigens is extremely small. Note also that because of the size of the BCG proteome, BLAST (rather than LALIGN, as in Figure 1 and Figure 2), was used to find these similarities, and a cut-off value for significance of E = 1.0 rather than 0.1 was used.

Figure 4

SARS-CoV-2 protein similarities with Bordetella pertussis polyprotein (UniProte accession number UP000002676). Note that whole B. pertussis is used as a vaccine. It is composed of 3260 proteins so that the probability that the matches shown are major antigens is extremely small. Note also that because of the size of the size of the B. pertussis proteome, BLAST (rather than LALIGN, as in Figure 1 and Figure 2), was used to find these similarities, and a cut-off value for significance of E = 1.0 rather than 0.1 was used, as was the case with M. tuberculosis (Figure 3) as well.